The role of AGEs in muscle ageing and sarcopenia

Guo Z, Li H, Jiang S, et al. The role of AGEs in muscle ageing and sarcopenia. Bone Joint Res. 2025;14(3):185-198. doi:10.1302/2046-3758.143.BJR-2024-0252.R1

Guo, Zhaojing, et al. “The role of AGEs in muscle ageing and sarcopenia.” Bone & Joint Research, vol. 14, no. 3, 2025, pp. 185-198., https://doi.org/10.1302/2046-3758.143.BJR-2024-0252.R1

Guo, Z., Li, H., Jiang, S., Rahmati, M., Su, J., Yang, S., Wu, Y., Li, Y., & Deng, Z. (2025). The role of AGEs in muscle ageing and sarcopenia. Bone & Joint Research, 14(3), 185-198. https://doi.org/10.1302/2046-3758.143.BJR-2024-0252.R1

Guo, Z., Li, H., Jiang, S., Rahmati, M., Su, J., Yang, S. et al. (2025) “The role of AGEs in muscle ageing and sarcopenia.” Bone & Joint Research, 14(3), pp. 185-198. Available at: https://doi.org/10.1302/2046-3758.143.BJR-2024-0252.R1

Guo, Zhaojing, Hengzhen Li, Shide Jiang, Masoud Rahmati, Jingyue Su, Shengwu Yang, Yuxiang Wu, Yusheng Li, and Zhenhan Deng. “The role of AGEs in muscle ageing and sarcopenia.” Bone & Joint Research 14, no. 3 (2025): 185-198. https://doi.org/10.1302/2046-3758.143.BJR-2024-0252.R1

Guo Z, Li H, Jiang S, Rahmati M, Su J, Yang S, et al. The role of AGEs in muscle ageing and sarcopenia. Bone Joint Res. 2025 Mar 4;14(3):185-198. https://doi.org/10.1302/2046-3758.143.BJR-2024-0252.R1

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Abstract

Sarcopenia is an ageing-related disease featured by the loss of skeletal muscle quality and function. Advanced glycation end-products (AGEs) are a complex set of modified proteins or lipids by non-enzymatic glycosylation and oxidation. The formation of AGEs is irreversible, and they accumulate in tissues with increasing age. Currently, AGEs, as a biomarker of ageing, are viewed as a risk factor for sarcopenia. AGE accumulation could cause harmful effects in the human body such as elevated inflammation levels, enhanced oxidative stress, and targeted glycosylation of proteins inside and outside the cells. Several studies have illustrated the pathogenic role of AGEs in sarcopenia, which includes promoting skeletal muscle atrophy, impairing muscle regeneration, disrupting the normal structure of skeletal muscle extracellular matrix, and contributing to neuromuscular junction lesion and vascular disorders. This article reviews studies focused on the pathogenic role of AGEs in sarcopenia and the potential mechanisms of the detrimental effects, aiming to provide new insights into the pathogenesis of sarcopenia and develop novel methods for the prevention and therapy of sarcopenia.

Cite this article: Bone Joint Res 2025;14(3):185–198.

Article focus

The pathogenic role of advanced glycation end-products (AGEs) in sarcopenia and the potential mechanisms of the detrimental effects.
A comprehensive review was conducted on the signalling pathways and molecular mechanisms through which AGEs contribute to sarcopenia development.

Key messages

By binding with receptor for advanced glycation end products (RAGEs), AGEs can activate a series of intracellular signalling pathways in skeletal muscle cells related to the elevated levels of inflammation and oxidative stress, as well as impaired insulin/insulin-like growth factor-1 (IGF-1) signalling and mitochondrial biogenesis, which lead to reduced protein synthesis, increased protein degradation, intracellular lipid accumulation, changes in fibre type composition and muscle energy metabolism, and a higher rate of apoptosis, finally resulting in muscle atrophy and impaired regeneration abilities.
Through directly targeted glycosylation, AGEs can damage the biological properties and functions of proteins which include the functional and structural proteins of skeletal muscle as well as collagens in ECM, resulting in muscle dysfunction such as impaired force production and increased stiffness. Furthermore, AGEs can also indirectly affect skeletal muscle by contributing to neuromuscular junction lesion and vascular disorders.

Strengths and limitations

This article explores the promoting effect of AGEs on the occurrence and development of sarcopenia, which provides new insights into the pathogenesis of sarcopenia and develops potential methods for the prevention and therapy of sarcopenia.
This article mainly reviews the basic research experiments, but there is a lack of discussion about clinical studies.

Introduction

Muscle ageing and sarcopenia

Skeletal muscle is one of the most vital organs in our body, accounting for approximately 40% of total body weight and containing 50% to 75% of total body proteins in humans. It plays a substantial role in maintaining our daily activities such as digestion, respiration, exercising, body posture maintenance, and joint and bone protection, among many other things.¹ Functioning as an important metabolic organ, skeletal muscle also contributes to the body’s balance of sugar and fat metabolism,² as it makes up 80% of body glucose clearance.³ Ageing muscle accompanies progressive muscle dysfunction such as muscle weakness and stiffness, presenting as low grip, slow movement, and decreased flexibility. Sarcopenia, namely the decline in muscle quality and function,⁴ represents the most remarkable and visual of all changes during the ageing process. Since 2016, it has been recognized as a disease, code ICD-10-CM (M62.84), by the World Health Organization (WHO)’s International Statistical Classification of Diseases and Related Health Problems (ICD).⁵ It refers to an asymptotic and systematic skeletal muscle disorder in the form of accelerated loss of muscle quality and function, which is linked to increased poor outcomes such as falls, fractures, frailty, cognitive decline, or even cardiovascular disease, leading to high hospitalization rates, elevated healthcare costs, and mortality.⁶ Muscle mass and strength (parallel to bone density) peak in early adulthood, and after a plateau begin to gradually decline; strength declines more rapidly, especially over the age of 75 years.⁷ With changing demographics and an ageing population, sarcopenia has gradually become a serious public health problem.⁶ In order to propose more effective measures to improve the treatment and prognosis of this disease, many studies focus on illustrating the pathophysiological process of sarcopenia, aiming to develop novel diagnostic biomarkers, nutrition interventions, and drugs which enhance the beneficial effects of exercise.⁶

AGEs and sarcopenia

Sarcopenia causes a decline in both the size and number of skeletal muscle fibres, and the main histological findings are the type 2 or fast-twitch muscle fibres decreasing, and a change in the skeletal muscle extracellular matrix (ECM) such as the substantial infiltration of fibrous and adipose tissue.^8,9 Specifically, the weakened ability for aged muscle to regenerate, repair, and remodel is a key aspect of sarcopenia.¹⁰ Ageing disturbs the homoeostasis of skeletal muscle, and multiple factors such as unbalanced protein metabolism, inflammation, oxidative stress, apoptosis, neuromuscular junction (NMJ) changes or motor neuron loss, satellite cell dysfunction, mitochondrial dysfunction, and microvascular changes can lead to sarcopenia.⁶

Advanced glycation end-products (AGEs), which originate from ‘glycation’ – a type of post-translational modification that usually occurs non-enzymatically and refers to a chemical reaction in which sugar binds to proteins, lipids, or nucleic acids – accumulate in various tissues in bodies with age and feature in the development of many chronic diseases such as obesity, diabetes, cardiovascular diseases (CVDs), osteoporosis, cognitive impairments, and cancer.¹¹ Many different types of AGEs exist in the human body, and over 20 different AGEs have been identified to date. These can be divided into fluorescent cross-linked AGEs, non-fluorescent cross-linked AGEs, and non-cross-linked AGEs. They have similarities in their biological efficacy, but there are also some slight differences. Currently, the most extensively studied AGEs are carboxymethyllysine (CML), pyrroline (both non-cross-linked), and pentosidine (fluorescent cross-linked).^11-13 In a cross-sectional analysis from 2,744 participants of northern European background whose mean age was 74.1 years, the authors found that higher skin AGEs were associated with a higher prevalence of sarcopenia.¹⁴ Additionally, according to several studies, elevated serum AGE levels have been reported to be associated with adverse sarcopenia-related outcomes, such as poor grip strength, slow walking speed, and increased muscle weakness.^15-18 Research has shown that AGE accumulation could occur around the muscle fibres, within the cells, or in the muscle fibres of extensor digitorum longus in aged rats.¹⁹ Although there is a lack of prospective studies to prove the causal relationship between AGEs and sarcopenia, the production and accumulation of AGEs in vivo is still recognized as a risk factor for the ageing-related loss of muscle mass and function, namely sarcopenia. AGEs are considered to cause or accelerate the pathological changes of sarcopenia based on partial current research,²⁰ and the mechanisms by which AGEs lead to sarcopenia are associated with the glycation-related cross-linking of intramuscular connective tissue and the raised levels of inflammation and oxidative stress in muscle caused by binding of AGEs to receptor for advanced glycation end products (RAGEs), followed by activating a string of intracellular signal transduction pathways.^21,22 The formation of AGEs is irreversible, and it is difficult for AGEs to decompose and metabolize in vivo. Currently, it is believed that the non-enzymatically regulated AGE cross-linking in collagenous tissues and the sustained activation of intracellular signalling pathways induced by the AGEs may be important reasons for the progressive development of sarcopenia.^11,21,23 This article mainly reviews the role of AGEs in the pathophysiological process of muscle ageing and sarcopenia, and aims to propose new insights into the pathogenesis and treatment methods of sarcopenia.

Formation and metabolism of AGEs

There are two sources of AGEs: endogenous and exogenous. Endogenous AGEs are a heterogeneous class of compounds derived from a series of glycosylation reactions. Maillard reaction is a non-enzymatic, multistep reaction, and occurs between the carbonyl group of a reducing sugar and the amino or N-terminal group of a protein or nucleic acid, such as adenine or guanine.²⁴ In the early stage of Maillard reaction, the condensation of the electrophilic carbon group of the reducing sugar with a free amino group (usually lysine or arginine) forms an unstable compound Schiff base, which is chemically unstable due to its rapid and reversible production.²⁵ Over the course of several weeks, the Schiff bases may slowly rearrange to form the more stable ketoamine (Amadori products).²⁵ Resulting from subsequent oxidation, dehydration, or polymerization reactions, Amadori products eventually produce very stable AGEs, and during the process reactive oxygen species (ROS) are also produced.²⁵ In addition to the Maillard reaction, the formation of AGEs under physiological conditions can occur through the reactive carbonyl pathway, which derives from glucose autoxidation, glycolysis intermediates, and lipid peroxidation (Figure 1).²⁶ AGEs continually form covalent bonds with free amino groups on adjacent proteins to produce AGE cross-linking, resulting in the reticulation of proteins and their cross-linking, which usually happens in the ECM and increases rigidity of tissues.^27,28 AGEs usually generate slowly and constantly in intracellular and extracellular environments, unless the organism in a state of ageing, inflammation, hyperglycaemia, or oxidative stress, when the rate of AGE accumulation is significantly accelerated.²⁸ In addition, AGEs can be formed exogenously, as a result of environmental factors such as diet and smoking. Direct intake of diets rich in AGEs substantially contribute to the AGEs in blood circulation. The formation of AGEs in food generally depends on several factors such as temperature, water content, pH status, cooking time, and method. Foods processed or chronically cooked or stored at high temperatures or pH, as well as fried or grilled foods, are all thought to contain plenty of AGEs.²⁴ It should be noted that apart from dietary AGEs, cigarette smoke has been reported to contain a certain amount of reactive glycation products, which pose a risk of increasing the accumulation of AGEs in the tissues and circulating blood of smokers.²⁹ The amounts of exogenous AGEs, which are thought to be closely related to the metabolism of AGEs in vivo,³⁰ are usually much higher than those of endogenous AGEs. Therefore, ingestion of food high in exogenous AGEs may cause more health problems than endogenous AGEs. Both types have similar biological functions, and thus can act analogously to stimulate inflammation, oxidative stress, and other cellular disturbance, leading to deleterious pathophysiological phenomena.²⁴

Fig. 1

Formation of advanced glycation end-products (AGEs).

The kidney and small intestine are the essential organs for metabolizing AGEs. Most orally administered dietary AGEs have two ways of leaving the body after they are directed to the gastrointestinal tract. Absorbable AGEs enter the bloodstream and their remains (about one-third of AGEs) are excreted through urine, while non-absorbable compounds enter the lower intestine where they are partially digested by gut microbiota and the remains are discharged from the body with faeces.³¹ The mechanism of the clearance of AGEs remains unclear, whereas available data suggest that AGEs, especially endogenously formed AGEs, are probably metabolized by either inborn defence or intracellular degradation after receptor-dependent uptake.³¹ The residual AGEs can cause many pathological changes in the body, including disrupting glucose metabolism homeostasis,³² exacerbating inflammatory response,³³ aggravating endothelial damage,³⁴ and escalating oxidative stress injury.³³

AGE-RAGE axis

Accumulating intracellularly and extracellularly in tissues and body fluids, AGEs can cross-link with certain macromolecules (such as proteins, nucleic acids, and lipids), thus the AGE-modified macromolecules undergo structural and functional alterations that do direct harm to their normal biochemical performance.³⁵ Besides the direct impact of AGEs on the ECM and proteins, AGEs regulate organismal pathophysiological functions principally through the AGE-RAGE axis pathway. RAGE exists on the cell surfaces of many tissues including heart, lung, and skeletal muscle.³⁶ Bound to AGEs to form the AGE-RAGE axis, RAGEs can activate intracellular signalling pathways and initiate a string of intracellular reactions. RAGEs are typically upregulated in muscles which are rich in the deposition of AGEs, since the deleterious effects of AGEs on muscle tissue are mediated in part by their interaction with RAGEs.³⁷ Known as a multiligand receptor, RAGE belongs to the immunoglobulin (Ig) superfamily (including Igs, cell surface receptors, and adhesion molecules).^38,39 RAGE is named for its interaction with AGEs, but its family of ligands includes AGEs, high mobility group box 1 (HMGB1), amyloid-P peptide, and S100 family members. Although typically expressed at low levels in normal tissues, RAGE is upregulated regardless of where its ligand accumulates.⁴⁰ AGE-RAGE interaction causes various physiological and pathological processes mediated by triggering intracellular signalling cascades. These signalling pathways include the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathway, p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated protein kinases 1 and 2 (ERK 1/2), and c-Jun N-terminal kinase (JNK), followed by the activation of nuclear transcription factor-κB (NF-κB) and interferon-stimulated response elements (ISRE).¹¹ After the activation of the NF-κB pathway, RAGE in turn gets a positive feedback effect in its expression, thus further accelerating the process of inflammation and becoming trapped in a vicious circle.⁴¹ The excessive amounts of AGEs lead to the overexpression of RAGE, and their ligation is supposed to cause further ROS production via the NAPDH pathway.⁴² Meanwhile, there is another class of AGE cell surface receptors that play a converse role compared with RAGE, and is involved in AGE detoxification, including macrophage scavenger receptors class A, type II (MSR-AII), and class B, type I (MSR-BI, CD36), as well as AGE receptors 1, 2, and 3 (AGE-R1, -R2, and -R3).^24,43 These receptors can mediate the catabolism and clearance of AGEs by modulating endocytosis and degradation.^44,45 For instance, the first identified AGE receptor, AGER1, possesses intrinsic anti-inflammatory properties that mediate oxidative stress reduction through three distinct mechanisms: 1) suppression of MAPK/NF-κB signalling pathway activity; 2) enhancement of AGE degradation; and 3) attenuation of cellular ROS production.^46-48 However, RAGE and AGE-R1 expression seems to depend positively and negatively on AGE levels. As observed in a study by Mastrocola et al,⁴⁹ the gastrocnemius muscle of high fructose diet (HFRT) mice that had a higher level of CML accumulation tended to have a higher level of RAGE expression and a lower level of AGE-R1 expression, in contrast with the control group.

Detrimental effects of AGEs to skeletal muscle

AGEs promote muscle atrophy

Muscle atrophy refers to the loss of muscle mass and strength, which is the consequence of an imbalance between skeletal muscle protein synthesis and degradation or changes in the functions of intramuscular proteins.⁵⁰ It is generally accepted that insulin/insulin-like growth factor-1 (IGF-1) signalling plays an important role in skeletal muscle protein synthesis.⁵¹ However, continuous low-grade inflammation, chronic increased oxidative stress, and impaired mitochondrial function are usually linked with skeletal muscle atrophy by accelerating protein degradation in skeletal muscle and damaging its energy supply. Meanwhile, ubiquitin proteasome system, autophagy lysosome system, caspase system, and calpain system are considered as the four major downstream pathways during the process.^50,52-54 Additionally, skeletal muscle atrophy is also correlated with other muscle alterations such as changes in myofibre types or myosin isoforms, as well as intramuscular and intermuscular fatty infiltration.^6,50,55

IGF-1 signalling is of great significance to maintaining skeletal muscle mass, and promotes protein synthesis by sequentially activating: phosphoinositide 3-kinase (PI3K); the serine/threonine kinase Akt, also known as protein kinase B (PKB); mammalian target of rapamycin (mTOR); and ribosomal protein S6 kinase, 70 kda (p70S6K).⁵¹ The impaired IGF-1 signalling of skeletal muscle could cause abnormal protein metabolism and finally lead to muscle wasting,⁵¹ while this process is partially related with the accumulation of AGEs in the body, especially in some conditions that promote AGE accumulation such as ageing and diabetes. A recent ex vivo experiment by Egawa et al⁵⁶ found that treatment with AGEs lowers the phosphorylation level of the majority of the phosphorylation sites in insulin/IGF-1 signalling. Such an effect has also been observed in their in vivo study, which showed that long-term AGEs intake in rodents reduced the phosphorylation of Akt and p70S6K.⁵⁶ Thus, they suggested that AGEs may play a part in ageing-related skeletal muscle loss by inhibiting protein synthesis through downregulating IGF-1 signalling. Additionally, Chiu et al⁵⁷ found that the accumulation of AGEs is associated with muscle atrophy and weakness in diabetic mice and elderly diabetic patients, showing a decrease in average muscle fibre cross-sectional area (CSA) and an increase in Atrogin-1/muscle atrophy F-box protein (MAFbx) compared with normal mice and the elderly, respectively. In their study, they used an OxiSelect AGE ELISA kit to assess the level of AGEs in serum, histological assessments, and western blot to detect the AGEs in skeletal muscle tissues and whole-cell protein extracts.⁵⁷ In further research, they proved that AGEs promote muscle atrophy in myotubes via a RAGE-mediated activation of AMP-activated protein kinase (AMPK), which leads to decreased Akt phosphorylation. The activated AMPK can increase protein degradation through the ubiquitin-proteasome pathway,⁵⁸ while Akt plays a role in protein synthesis,⁵⁹ both of which promote the catabolism of muscle protein and result in the reduction of muscle tube size. However, this process could be drastically reversed by treatment with Ala-Cl (an AGEs cross-link breaker), sRAGE (the soluble circulating form of RAGE), IGF-1, and compound C (an AMPK inhibitor).⁵⁷ The reduction of the sensitivity of target tissue to insulin, defined as insulin resistance, is the major characteristic of type 2 diabetes,^60,61 which certainly has negative effects on skeletal muscle since it accounts for a considerable part of total body protein and glucose clearance.⁶² The increased formation of AGEs in the body under a circumstance of chronic hyperglycaemia seems to intensify insulin resistance.^63,64 Cassese et al⁶³ found that human glycated albumin (HGA) could induce the formation of a multimolecular complex consisting of RAGE, protein kinase C α (PKCα), and Src in L6 cells; this phenomenon has also been observed in skeletal muscle from the dietary insulin-resistant high-AGE diet (HAD) fed mice. Further, the activated PKCα and Src may suppress insulin action through the serine/threonine phosphorylation of insulin receptor substrate (IRS), as observed in L6 cells.^63,65 Therefore, AGEs may inhibit insulin action in skeletal muscle cells by the formation of this RAGE/IRS-1/Src/PKCα complex ex vivo and probably in vivo. However, an interesting study proposed a novel methylglyoxal (a highly reactive AGEs precursor)-derived AGEs inhibitor, MK-I81, which could regain insulin sensitivity and alleviate the effect of insulin resistance caused by AGE-mediated downregulation of insulin signal transduction in skeletal muscle to an extent;⁶⁶ this is a potential therapeutic compound for the future.

Muscle homeostasis can be influenced under a circumstance of low-grade chronic inflammation, which has been reported to suppress antagonist muscle activation and contribute to age-related muscle weakness.⁶⁷ With ageing, the amassing of AGEs and the expression of RAGE in muscle tissue were pathologically increased,¹ which would also happen in other cells that express RAGE like monocytes, resulting in a sustained activation and release of proinflammatory factors and contributing to the systemic chronic low-grade inflammatory state.⁴⁰ The AGE-RAGE interaction can activate NF-κB, and subsequently leads to the increased expression of numerous inflammatory gene products and the establishment of an inflammatory niche.^68,69 Inflammatory mediators upregulated by AGE-RAGE-NF-κB pathways include tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and CRP.⁷⁰ These inflammatory factors also activate the NF-κB pathway, further raising inflammation levels and thereby reactivating the ubiquitin-proteasome system (UPS) and autophagolysosomal system, leading to protein degradation.⁷¹ High levels of TNF-α could stimulate myostatin expression through a NF-κB-dependent pathway, while the exposure to myostatin could induce production of IL-6.⁷² Excess IL-6 could induce the dephosphorylation of Akt thus inhibiting its activation, resulting in increased protein degradation and decreased protein synthesis in muscle.^72,73 Myostatin, a member of the transforming growth factor-β (TGF-β) family of secreted proteins, is mainly expressed in skeletal muscle, and can be activated by proteolysis or free radical stimulation and induce muscle loss. The excessive released myostatin can bind to the high-affinity type 2 activin receptor (ActRIIB) on the sarcolemma, leading to the activation of type 1 activin receptor serine kinases ALK4 or ALK5, which phosphorylate Smad2/3 thus stimulating the gene transcription linked with UPS.^50,74 Moreover, application of TNF-α has been proved to initiate the apoptotic signalling pathways in the mature cultured muscle cells, thus promoting catabolism.⁷⁵ Further, inflammatory cytokines can also deactivate the PI3K/Akt/mTOR pathway, mediating insulin resistance thus resulting in the reduction of protein synthesis.^74,76 Reduced Akt dephosphorylation stimulates muscle proteolysis by activating caspase-3 and UPS, since caspase-3 produces substrates for UPS cleaving actomyosin and increases proteasoma-mediated proteolysis. Additionally, the activation of forkhead box O3 (FOXO3) after activation of the NF-κB pathway can induce the expression of the muscle-specific ubiquitin ligases atrogin-1/MAFbx and muscle RING finger-1 (MuRF-1), and at the same time autophagy-associated proteins (Atgs), leading to selective proteolysis of myosin and other thick filament proteins, as well as actin and other thin filament proteins.^76-79 Inflammatory cytokines can also induce cyclooxygenase-2 (COX-2), which plays a part in skeletal muscle cachexia.⁸⁰ It is reported that increased COX-2 messenger RNA (mRNA) expression is followed by upregulated MuRF1 and atrogin-1 expression in the gastrocnemius of rats.⁸¹

Oxidative stress is another considerable factor linked with age-related muscle wasting. Research work has demonstrated that muscle tissue from those with obesity and older subjects showed increases in immunostaining of CML and RAGE, which was positively correlated with immunostaining of markers of oxidative stress and inflammation.⁸² Oxidative stress refers to a state that means the imbalance of oxidative and antioxidative effects in vivo, which usually results from a rise in ROS and a reduction in antioxidant function.⁸³ The age-related decline in cellular antioxidant defences, coupled with elevated ROS production and compromised clearance mechanisms, leads to a progressive net accumulation of ROS within biological systems over time.⁸⁴ ROS are involved in AGE synthesis through glycoxidation, which promotes the synthesis of highly reactive carbonyl intermediates such as glyoxal and methylglyoxal, which can further react with different molecules to produce AGEs.⁸⁵ ROS contribute to skeletal muscle atrophy through a series of ways: activating the UPS and leading to the waste of muscle mass through intensifying proteolysis and reducing muscle protein synthesis; reducing the calcium release from sarcoplasmic reticulum by impairing excitation-contraction coupling; inducing modifications of actin and myosin structures; and dramatically decreasing the cross-bridge cycling within the myofibrillar apparatus.^85,86 Besides, there are other common cell damages caused by ROS such as mitochondrial damage, cellular apoptosis, inflammation, and lipid peroxidation.⁸⁷ The AGE-RAGE interaction increases oxidative stress by activating NADPH oxidase, which is a main source of ROS and could cause NF-κB stimulation.^42,88 ROS can also activate NF-κB through the Ras-ERK1/2 and Rac1-MKK6 pathways, and can accelerate muscle protein damage through a Ca²⁺-dependent pathway.⁸⁹ Besides, binding of AGE-RAGE also facilitates oxidative stress through other pro-oxidative stress pathways such as protein kinase C (PKC) pathways.⁹⁰ It has been reported that elevated activities of the PKC pathway could stimulate ROS-generating enzymes such as NADPH oxidases and lipoxygenases; both of them can aggravate the cellular oxidative environment.⁹¹ Cai et al⁹² found that the skeletal muscle of mice with long-term oral methylglyoxal-AGE showed severe deficiency of AGE-R1 and survival factor sirtuin 1 (SIRT-1), elevating basal oxidative stress/inflammation and increasing susceptibility to metabolic abnormalities of insulin resistance. Worse still, the stronger oxidative environment will further accelerate the formation of AGEs, leading to a vicious circle.¹¹ Blocking the receptor for RAGEs enhances antioxidant capacity, as it has been verified in a previous study that RAGE-deficient mice have an increased superoxide dismutase and sirtuin mRNA expressions.⁹³ Moreover, high oxidative stress may also promote muscle atrophy through upregulating myostatin, which has been observed in chronic kidney disease (CKD).⁹⁴

Mitochondria are extremely important organelles for skeletal muscle, since they participate in the regulation of many critical cellular processes such as energy provision, calcium homeostasis, ROS production, and regulation of apoptosis.⁹⁵ Mitochondrial respiratory dysfunction, reduced muscle mitochondrial mass, and reduced skeletal muscle energy supply all contribute to the development of muscle atrophy. Plenty of evidence indicates that AGEs do harm to mitochondrial respiration and oxidative phosphorylation, while the downstream effects caused by AGE-RAGE binding may play a significant role in this process. Some studies carried out in cardiomyocyte mitochondria may provide further evidence for this. For instance, incubation of AGEs in different cell lines promoted the dissipation of Δψm and the reduction of intracellular adenosine triphosphate (ATP) levels, while the RAGE null mice had higher cardiac ATP levels than their littermates.⁴³ Additionally, compared with the normal high-fat diet mice, RAGE-deficient mice showed better mitochondrial quality control by facilitating removal of damaged mitochondria.⁹³ AGEs and ROS can be induced by reducing oxidase and mitochondrial protein oxidation change to influence mitochondrial function, leading to protein degradation and loss of function and mitochondrial volume density and mitochondrial DNA copy number of reduction.⁹⁶ Moreover, AGE-induced oxidative stress and inflammation may do damage to mitochondrial biogenesis.⁹⁶ Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is thought to play the most important cooperative role in mitochondrial biogenesis, and is viewed as a marker of mitochondrial biosynthesis.⁹⁷ PGC-1α and mitochondrial protein content in skeletal muscle have been reported to decrease with age,⁹⁸ while oxidative stress and inflammation decrease PGC-1α expression and increase the mitochondria number in muscle.⁹⁹ Yabuuchi et al³⁷ found that AGEs-aptamer ameliorated the reduction of succinate dehydrogenase (SDH) activity and PGC1-α in the gastrocnemius muscle of 5/6 Nx CKD model mice, which implies that AGE may cause deteriorating effects on mitochondrial energy production and biosynthesis in part by lowering SDH activity and PGC1-α levels. Similarly, Mastrocola et al⁴⁹ found that mean SDH activity per oxidized muscle fibre was reduced in HFRT mice compared with the mice fed a standard diet, which could be improved by the supplement of pyridoxamine, a potent inhibitor of the dicarbonyl compound precursor of AGEs. The hypothesis of fructose-derived AGE-induced mitochondrial damage had been verified by further assays, which showed reduced mitochondrial membrane potential in HFRT gastrocnemius muscle as well as reduced sarcomere mitochondrial creatine kinase (sMtCK) content in HFRT gastrocnemius muscle extracts.⁴⁹ However, pyridoxamine treatment could almost totally reverse this AGE-induced mitochondrial damage.⁴⁹

Apart from the above points, AGEs can also promote muscle atrophy through the following mechanisms. First, AGEs can directly target skeletal muscle intracellular proteins to change their biological functions. AGEs generated in the Maillard reaction, while changing the structure and activity of proteins, also reduce their susceptibility to degradation.^100,101 Snow et al¹⁹ observed the number and types of age-modified proteins in the extensor longus muscle of young (eight months), old (33 months), and very old (36 months) rats. According to their study, intracellular proteins creatine kinase, β-enolase, carbonic anhydrase III, and voltage-dependent anion selective channel 1 (VDAC1) are targets for AGEs, and are of great importance to skeletal muscle energy supply. In addition, structural proteins of skeletal muscle are also targets for AGEs, as the actin has been identified by the AGE immunoreactive bands.¹⁹ The AGE-modified actin reduces actin polymerization, thus having a detrimental effect on myofibril contraction.^102,103 Ramamurthy et al¹⁰⁴ found that glucose reduced the speed of myosin movement in a dose-dependent manner, while glutathione reversed the effects of glucose on myosin function. Glycosylation of myofibrils (myosin, actin) has been reported to reduce adenosine triphosphatase (ATPase) activity in an ex vivo experiment.¹⁰⁵ Additionally, targeting glycosylated respiratory chain complex I and IV components and catalase will impair cellular energy metabolism and the entire antioxidant defense system, respectively.⁴³ Second, AGEs can contribute to lipid accumulation in muscle cells. A study by Mastrocola et al⁴⁹ showed that there is a higher level of triglyceride, and the adipogenic sterol-regulatory element binding protein (SREBP) cleavage-activating protein SCAP/SREBP pathway is strongly activated in the skeletal muscle homogenate of HFRT mice compared with the standard diet mice. As SIRT-1 was viewed as the inhibitor of SREBP-1c activity and could be upregulated by AGE-R1,¹⁰⁶ the authors found that HFRT diet can reduce not only the levels of AGE-R1 but also expression of SIRT-1, while both could be effectively prevented by pyridoxamine treatment.⁴⁹ Third, AGEs may cause changes in fibre type composition and muscle metabolism. Since the myogenic regulatory factors (MRFs) involved in muscle structural protein reprogramming were thought to be regulated by the activity of SREBP-1c,¹⁰⁷ AGEs may contribute to age-related muscle fibre switch. Uribarri et al¹⁰⁶ found that in the gastrocnemius muscle of HFRT mice, there was a higher content of slow-switch fibre of myosin heavy chain (MyHC) 1 and 2 and a lower content of fast glycolysis fibre of MyHC2b, which impaired the contractile function of the muscle as a whole. However, pyridoxamine had also been found in their study to effectively preserve the composition of MyHC.¹⁰⁶ The molecular mechanisms of AGEs leading to skeletal muscle atrophy are summarized in Figure 2.

Fig. 2

Molecular mechanisms of advanced glycation end-products (AGEs) leading to skeletal muscle atrophy. Arrows (→) indicate activation and stub lines (T) indicate inhibition. ActRⅡB, type 2 activin receptor; Akt, serine/threonine kinase; ALK4/5, activin receptor-like kinase 4/5; AMPK, adenosine 5‘-monophosphate; CAⅢ, carbonic anhydrase III; CK, creatine kinase; FOXO3, fork head box O3; IGF-1, insulin-like growth factor-1; IGFR, receptor for IGF-1; IR, receptor for insulin; mTOR, mammalian target of rapamycin; Murf1, muscle RING finger-1; NADPH, nicotinamide adenine dinucleotide phosphate; NF-kB, nuclear factor-κB; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; RAGE, receptor for AGEs; ROS, reactive oxygen species; Smad2/3, mothers against decapentaplegic 2/3; SIRT1, sirtuin1; UPS, ubiquitin-proteasome system; VDAC1, voltage-dependent anion selective channel 1. Created with BioRender.com, with permission.

AGEs impair muscle regeneration

Satellite cells (SCs) play a central part in skeletal muscle regeneration. When skeletal muscle is damaged, they can be activated and become myoblasts that differentiate into myocytes. Myocytes fuse to form myotubes or integrate with existing muscle fibres to regenerate skeletal muscle.³⁵ Pax7 (pairing domain transcription factors) and MRFs are in regulation of myogenesis. Pax7 is expressed and labelled in resting stem cells (SCs) to prevent their premature differentiation, which is important for the proliferation and survival of myogenic progenitors. In myoblasts, the expression of Pax7 and myogenic regulatory factors (MRFs) demonstrates mutual exclusivity, as downregulation of Pax7 is required to enable terminal differentiation of muscle cells.¹⁰⁸ MRFs (namely Myf5, MyoD, myogenin, and MRF4) are activated timely in myoblasts to modulate downstream targets such as MyHC, MCK (creatine kinase), and troponin T, which are required for terminal differentiation and functional muscle fibre generation.^109,110

RAGE signalling plays a significant role in skeletal muscle regeneration, especially in the process of acute damage in skeletal muscle.⁷⁶ During the early stages of differentiation, activated myoblasts respond to S100B via RAGE to enhance proliferation via ERK1/2, and simultaneously initiate myogenic processes via p38 MAPK.¹¹¹ During the later stages of differentiation, HMGB1 stimulates the upregulation of myogenin through the RAGE-dependent p38 MAPK pathway, preparing for myoblast fusion by inhibiting Pax7.¹¹² However, when the AGEs are pathologically upregulated under certain circumstances such as ageing, high glucose conditions, or long-term chronic high levels of inflammation and oxidative stress, the pathologically upregulated AGE-RAGE signalling dominates the natural RAGE course, leading to the abnormal differentiation of SCs.⁷⁶ Chiu et al⁵⁷ witnessed that AGEs impaired the regeneration of damaged muscle in the mice and stimulated collagen deposition in the regenerated muscle. AGE-BSA (bovine serum albumin) treatment reduces myogenic protein and MyHC expression through phosphorylation of AMPK and dephosphorylation of Akt, thereby adversely affecting myoblast differentiation and fusion, which can be reversed by the treatment of Ala-Cl, sRAGE, IGF-1, and compound C.⁵⁷ Takata et al¹¹³ found that AGEs derived from glyceraldehyde (an intermediate of glucose/fructose metabolism) strongly induced C2C12 cell death, manifested as the vitality of C2C12 cells treated with glyceraldehyde dropped in a dose-dependent manner. However, this detrimental effect can be completely inhibited by pretreatment with aminoguanidine, a depressant of AGE production. Similarly, Adachi et al¹¹⁴ found that both AGE2 and AGE3, derived from glyceraldehyde and glycolaldehyde, respectively, could apparently inhibit the mRNA expression of MyoD, myogenin, endogenous IGF-1, and total Akt in C2C12 cells, and all these conditions could be reversed by co-treatment with IGF-1. In addition, treatment with AGE2 and AGE3 greatly promoted the apoptosis of C2C12 cells, while co-incubation of IGF-I with AGE2 or AGE3 counteracted the cytotoxic effects of AGE2 and AGE3.¹¹⁴ Furthermore, the authors found that a hyperglycaemia environment accelerates the impairment of AGEs through upregulating the expression of RAGE.¹¹⁴ Similarly, a study by Tanaka et al¹¹⁵ found that AGE2 or AGE3 treatment could suppress the myoblastic differentiation of C2C12 cells, probably by suppressing the expression of MyoD and myogenin proteins in C2C12 cells, while 1,25D (a sort of active vitamin D) could, to an extent, reverse such harmful effects. Apart from the SCs, human mesenchymal stem cells (MSCs) may also have a role in differentiating into mature musculoskeletal tissues after tissue damaging. Research by Kume et al¹¹⁶ showed that treatment with AGEs could inhibit MSC proliferation, induce apoptosis, and prevent cognate differentiation, which might result in the loss of MSC mass which would manifest as tissue repair disorders. They also found that this detrimental effect of AGEs on MSCs may be partially attributed to the AGE-RAGE interaction, since the antiserum against RAGE discouraged the AGE-induced MSC events to a certain extent.¹¹⁶ Although many studies have shown the association between AGEs and impaired muscle regeneration ability, there are few studies that have focused on the specific molecular mechanisms. STAT3 signalling is known to be upregulated in older SCs, while suppression of it might lead to an increasing number of SCs, which is conducive to the repair of muscle tissue and improved functional performance.¹¹⁷ A study by Egawa et al⁵⁶ found that AGE treatment increased STAT3 Tyr705 phosphorylation in skeletal muscle, which was verified in both in vivo and ex vivo experiments, presenting that AGE-induced suppression of muscle regeneration may be partially through activation of STAT3 signalling. Additionally, ERK, as a member of the mitogen-activated protein kinase family and involved in the differentiation of skeletal muscle cells,¹¹⁸ also plays a crucial regulating role in myogenesis.¹¹⁹ Egawa et al⁵⁶ found that the presence of AGEs exacerbated the age-related attenuation of ERK signalling, since they observed that the AGE treatment decreased ERK Thr202/Tyr204 phosphorylation in C2C12 cells, and the long-term AGEs intake also lowered the ERK phosphorylation in rat skeletal muscle.

AGEs disrupt the normal structure of skeletal muscle ECM

Skeletal muscle ECM is of great significance for the transmission, maintenance, and adjustment of muscle fibre force.¹²⁰ The ECM of skeletal muscle is usually divided into endomysium, perimysium, and epimysium, which is a connective tissue scaffold surrounding individual muscle fibres, muscle bundles, and the entire muscle.^21,120 The principle composition of skeletal muscle ECM is collagen. This provides a scaffold for remaining muscle-tendon integrity and is involved in the transmission of muscle force, as the elastic properties of collagen are partly responsible for the production of passive force in skeletal muscle.¹²¹

Since the formation of AGEs is a lengthy stochastic process that depends on the concentration and probability of monosaccharides in an open-loop conformation, it is easier for AGEs to accumulate in long-lived proteins such as collagen.^122,123 Moreover, collagen contains lots of lysine and arginine amino acids, which potentiates AGE formation.¹²² Previous research shows that glycosylation of myofibrillar proteins increases with age,¹²⁴ and locally formed AGEs can change the biomechanical properties of skeletal muscle, increasing stiffness and decreasing elasticity through cross-linking in the connective tissue, making it more resistant to enzymatic degradation, and finally impairing the muscle and body functions.^69,125 Differing from enzymatically mediated collagen cross-linking such as non-reducing collagen pyridinium cross-links, non-enzymatically regulated AGE cross-linking is another form of biochemical linkage that results from the spontaneous non-enzymatic bond formed between a reducing sugar and a protein residue.²¹ Once formed, AGEs can only be metabolized if the proteins to which they are linked are degraded.¹²⁶ The increases in collagen concentration, pyridine cross-linking of hydroxycollagen, and AGE cross-linking have been reported to closely relate to increased muscle rigidity and reduced muscle flexibility, since the increased AGE cross-linking can harm the elastic properties of collagen thus affecting the passive viscoelastic properties of skeletal muscle.^{69,121,125,127} Research by Haus et al²¹ confirmed that intramuscular collagen concentration and enzyme-mediated collagen cross-linking are under rigorous regulation, as similar concentrations are observed in the skeletal muscle of young and old individuals. In contrast, AGE cross-linking in muscle has been observed to increase in healthy, sedentary older adults. In their study, the authors witnessed a 200% increase of pentose glycoside in the elderly which may have affected the stiffness of the tissue and the passive viscoelastic properties of the muscle, thereby contributing to the decline in muscle function.²¹ Bartling et al¹²⁸ had demonstrated that AGE-collagens impair efficient cell adhesion and migration, as well as matrix degradation since collagen proteolysis and AGE level of the individual collagen samples showed an inverse correlation. However, during tensile loading, the cross-linked collagen triple helix undergoes local micro-unfolding, thereby increasing the number of proteolytic sites as well as susceptibility to collagenase digestion.¹²⁹ Thus, the accumulation of AGEs in skeletal muscle may be partially attributed to the decline of collagen turnover rate, which may result from the lack of a regular and robust tissue turnover stimulus such as exercise.^130,131 In their study, Maessen et al¹³⁰ made a comparison of dicarbonyl stress and AGEs in lifelong endurance athletes (ATH) versus sedentary controls. Their study found that ATH tend to have lower levels of dicarbonyl stress while have higher levels of circulating AGE markers such as CML and carboxyethyllysine (CEL), thus they proposed a possible explanation that exercise improves collagen turnover, which breaks and prevents AGE cross-linking in the tissue, leading to larger amounts of circulating AGEs.

AGEs contribute to neuromuscular junction lesion and vascular disorders

The NMJ is the synapse between an α motor neuron and a skeletal muscle fibre, which is a microenvironment under strict modulation.¹²³ However, impaired NMJ can influence the stability of the microenvironment of synapse, or even cause the collapse of the motor unit spatial domain, presenting as the low speed of muscle contraction and loss of muscle strength.¹³² During the maturation process of NMJ, the microenvironment in the region of the motor end plate comprises mostly of collagen type IV and laminin; it is under careful regulation and thought to participate in NMJ development.¹²³ A previous study showed that non-enzymatic glycosylation of laminin inhibited neurite outgrowth in cultured neuroblastoma cells.¹³³ It has been shown that at high glucose concentrations, non-neuronal cells derived from the sciatic nerve express elevated mRNA levels of fibronectin and collagen types I and IV,¹³⁴ and increased collagen IV synthesis may form massive microfibril deposits between the perineurial cell layers.¹³⁵ At the same time, deposition of collagen fibres themselves may also prevent nerve regeneration.¹³⁶ Furthermore, glycated collagen is suggested to increase under diabetic conditions and be resistant to protease digestion, which may do harm to axon regeneration, thereby contributing to neuropathy in diabetic patients.¹³⁶ Collagen deposition around neurones may act as a compressive lesion or, on the other hand, may interfere with diffusion, transport, and binding of neuropeptides and monoamines.¹²⁵ In short, it is clear that NMJ lesions can be driven by AGE-cross-linked ECM components. Furthermore, it has been reported that AGEs exhibit high cytotoxicity on Schwann cells through P38 MAPK and NF-κB pathways, which could lead to the demyelination of the motor nerves.^137,138 Moreover, deposition of AGEs would enhance local oxidative stress and produce more ROS that act on NMJ. Specifically, ROS were suggested to prevent the generation of an action potential of the sarcolemma by reducing acetylcholine release in synaptic cleft, and persistent oxidative stress has been thought to reduce the amount of innervation and fibres, thus altering the morphology of the NMJ.⁸⁵

A healthy vasculature surrounding skeletal muscle is designed to ensure its nutrient supply and waste product removal.³ AGE accumulation is associated with micro- and macrovascular disorders, which may do harm to skeletal muscle metabolism and regeneration.^3,139 AGEs have been reported to affect the vascular endothelium by inducing adverse biological events such as foam cell formation, calcium deposition, inflammation, oxidative stress, and apoptosis; these processes together lead to vascular calcification and progression of atherosclerotic plaques.¹⁴⁰ Koike et al¹⁴¹ demonstrated that AGE-induced apoptosis of vascular smooth muscle cells (VSMCS) could be the result of NADPH oxidase activation and ROS generation. Moreover, Otero et al¹⁴² found that albumin-derived AGEs could disrupt the vascular endothelial cadherin (VE-cadherin) complex in cultured human and murine endothelial cells (ECs), one of the most important regulators of EC integrity and intercellular communication,¹⁴³ while the loss of VE-cadherin complex components was linked to increased vascular permeability and EC migration, leading to the unstable adhesion of ECs.³⁴ The microvascular system is of great importance to maintaining the delivery of oxygen and nutrients of skeletal muscle, especially during periods of increased activity. Capillary rarefaction may lead to skeletal muscle fatigue,³⁴ as a lower capillary-to-fibre ratio was observed in biopsy samples of the lateral thigh muscle from haemodialysis patients who showed impaired exercise capacity.¹⁴⁴ A study by Yabuuchi et al³⁷ found that the AGE-aptamer could, to an extent, restore the capillary rarefaction in the gastrocnemius muscle of 5/6 Nx CKD mice. Asymmetric dimethylarginine (ADMA) is an endogenous depressant of nitric oxide (NO) synthase that is correlated with endothelial disability.¹⁴⁵ Plasma ADMA levels were negatively correlated with endothelial function, as measured by flow-mediated vasodilation, but increased with serum AGE levels.¹⁴⁵ Ando et al¹⁴⁵ found that AGEs decreased mRNA levels of dimethylarginine dimethylaminohydrolase (DDAH)-II, an ADMA degrading enzyme, and decreased its total enzyme activity thereby increasing ADMA, which may contribute to ROS generation mediated by AGE-RAGE signalling in ECs, while these effects could be completely blocked by the antioxidant N-acetylcysteine. Thus, the AGEs may contribute to capillary rarefaction and ischaemia in the skeletal muscle mediated by ADMA through reducing NO synthesis and bioavailability.

Conclusion and future prospects

The accumulation of AGEs in the body can accelerate the progression of sarcopenia in many ways. In this article, we reviewed the potential mechanisms of the detrimental effects based on existing studies. On the one hand, by binding with RAGE, AGEs can activate a series of intracellular signalling pathways in skeletal muscle cells related to the elevated levels of inflammation and oxidative stress, as well as impaired insulin/IGF-1 signalling and mitochondrial biogenesis, which leads to reduced protein synthesis and increased protein degradation, intracellular lipid accumulation, changes in fibre type composition, and muscle energy metabolism as well as a higher rate of apoptosis, finally resulting in muscle atrophy and impaired regeneration abilities. On the other hand, by directly targeted glycosylation, AGEs can damage the biological properties and functions of proteins that include the functional and structural proteins of skeletal muscle and collagens in ECM, resulting in muscle dysfunction such as impaired force production and increased stiffness. In addition, AGEs can also indirectly affect skeletal muscle by contributing to NMJ lesions and vascular disorders (Figure 3).

Fig. 3

The pathogenic role of advanced glycation end-products (AGEs) in skeletal muscle. ECM, extracellular matrix; NMJ, neuromuscular junction. Created with BioRender.com, with permission.

Since AGEs are a link in the pathophysiological process of muscle ageing and sarcopenia, there are some corresponding measures and treatments that people can take to prevent its progression. Limiting the exogenous intake of AGEs is of great importance, and specific measures include reducing intake offried or baked food, a low-fat and low-sugar diet, quitting smoking, and adding lemon or vinegar to lower the local pH of food.^29,146 AGE precursor-derived AGE formation inhibitors such as aminoguanidine,¹¹³ pyridoxamine,⁴⁹ and MK-I81⁶⁶ have been reported to be effective in alleviating the toxicity of AGEs by reducing their endogenous formation. A previous study in animal models showed that AGE cross-link breakers (e.g. Ala-Cl) and soluble circulating RAGE are effective in reducing AGE accumulation in tissues,⁵⁷ but whether it can be applied in clinic needs further verification. Ex vivo experiments have demonstrated that IGF-1, compound C, and 1,25D are effective in decreasing myotube atrophy and recovering the regeneration activities of skeletal muscle cells,^57,115 which may offer a way of thinking to novel therapy development. Suppressing the activity of RAGE seems to be an effective way to avoid part of the toxic effects of AGEs, control inflammation and oxidative stress levels, and protect the skeletal muscle to some extent.⁷⁶ Some RAGE inhibitors such as TTP488¹⁴⁷ and FPS-ZM1¹⁴⁸ have been developed and were well tolerated in human trials, and both have been reported to reduce or abrogate the pathogenic effects caused by RAGE activity by reducing AGE-RAGE interactions in animal models. However, the application of RAGE inhibitors still needs further clinical studies to guarantee its effectiveness, and determine the appropriate dose since the complete inhibition of RAGE may damage the regeneration of skeletal muscle.⁷⁶ Exercise is a well-established and effective way to reverse or delay the progression of sarcopenia, which could get further support from the useful effects of exercise on decreasing the AGE-induced detrimental effects on skeletal muscle. One mechanism by which exercise reduces AGE accumulation is improving glucose tolerance and lipid levels, to reduce the raw materials of the glycation response such as sugars and aldehydes.²⁰ Moreover, exercise can enhance AGE degradation by stimulating protein turnover, especially the collagen in the ECM of skeletal muscle, thereby improving muscle flexibility by reducing AGE cross-linking.^130,131 It has also been reported that exercise could reduce AGE-RAGE binding by reducing RAGE expression,¹⁴⁹ and increase the gene expression of enzymes responsible for the degradation of precursor glycosylation product.¹⁵⁰ Furthermore, exercise is effective in counteracting the pro-inflammation and pro-oxidative stress effects of AGEs.¹⁵¹ Exercise also inhibits myostatin signalling, thereby repressing the transcription of atrogenes and reducing the consequent protein degradation.¹⁵¹ Moreover, exercise can stimulate protein synthesis by increasing the internal IGF-1 levels and promote mitochondrial biogenesis by inducing the transcription of PGC-1α.¹⁵¹ The specific mechanism of AGEs involved in the occurrence and development of sarcopenia needs to be further elucidated, in order to facilitate further research and develop treatment methods and drugs for sarcopenia.

Correspondence should be sent to Zhenhan Deng. E-mail: dengzhenhan@wmu.edu.cn

Z. Guo and H. Li contributed equally to this work.

Y. Wu, Y. Li and Z. Deng are joint senior authors.

Z. Guo and H. Li are joint first authors.

References

1. Zhong Q , Zheng K , Li W , et al. Post-translational regulation of muscle growth, muscle aging and sarcopenia . J Cachexia Sarcopenia Muscle . 2023 ; 14 ( 3 ): 1212 – 1227 . Crossref PubMed Google Scholar

2. Sousa-Victor P , García-Prat L , Muñoz-Cánoves P . Control of satellite cell function in muscle regeneration and its disruption in ageing . Nat Rev Mol Cell Biol . 2022 ; 23 ( 3 ): 204 – 226 . Crossref PubMed Google Scholar

3. Mesinovic J , Zengin A , De Courten B , Ebeling PR , Scott D . Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship . Diabetes Metab Syndr Obes . 2019 ; 12 : 1057 – 1072 . Crossref PubMed Google Scholar

4. Larsson L , Degens H , Li M , et al. Sarcopenia: aging-related loss of muscle mass and function . Physiol Rev . 2019 ; 99 ( 1 ): 427 – 511 . Crossref PubMed Google Scholar

5. Anker SD , Morley JE , von Haehling S . Welcome to the ICD-10 code for sarcopenia . J Cachexia Sarcopenia Muscle . 2016 ; 7 ( 5 ): 512 – 514 . Crossref PubMed Google Scholar

6. Cruz-Jentoft AJ , Sayer AA . Sarcopenia . Lancet . 2019 ; 393 ( 10191 ): 2636 – 2646 . Crossref PubMed Google Scholar

7. Ferrucci L , de Cabo R , Knuth ND , Studenski S . Of Greek heroes, wiggling worms, mighty mice, and old body builders . J Gerontol A Biol Sci Med Sci . 2012 ; 67 ( 1 ): 13 – 16 . Crossref PubMed Google Scholar

8. Schiaffino S , Reggiani C . Fiber types in mammalian skeletal muscles . Physiol Rev . 2011 ; 91 ( 4 ): 1447 – 1531 . Crossref PubMed Google Scholar

9. Walston JD . Sarcopenia in older adults . Curr Opin Rheumatol . 2012 ; 24 ( 6 ): 623 – 627 . Crossref PubMed Google Scholar

10. Joanisse S , Nederveen JP , Snijders T , McKay BR , Parise G . Skeletal muscle regeneration, repair and remodelling in aging: the importance of muscle stem cells and vascularization . Gerontology . 2017 ; 63 ( 1 ): 91 – 100 . Crossref PubMed Google Scholar

11. Chen J-H , Lin X , Bu C , Zhang X . Role of advanced glycation end products in mobility and considerations in possible dietary and nutritional intervention strategies . Nutr Metab (Lond) . 2018 ; 15 ( 1 ): 72 . Crossref PubMed Google Scholar

12. Luevano-Contreras C , Chapman-Novakofski K . Dietary advanced glycation end products and aging . Nutrients . 2010 ; 2 ( 12 ): 1247 – 1265 . Crossref PubMed Google Scholar

13. Ahmed N . Advanced glycation endproducts--role in pathology of diabetic complications . Diabetes Res Clin Pract . 2005 ; 67 ( 1 ): 3 – 21 . Crossref PubMed Google Scholar

14. Waqas K , Chen J , Trajanoska K , et al. Skin autofluorescence, a noninvasive biomarker for advanced glycation end-products, is associated with sarcopenia . J Clin Endocrinol Metab . 2022 ; 107 ( 2 ): e793 – e803 . Crossref PubMed Google Scholar

15. Mori H , Kuroda A , Ishizu M , et al. Association of accumulated advanced glycation end-products with a high prevalence of sarcopenia and dynapenia in patients with type 2 diabetes . J Diabetes Investig . 2019 ; 10 ( 5 ): 1332 – 1340 . Crossref PubMed Google Scholar

16. Mori H , Kuroda A , Araki M , et al. Advanced glycation end-products are a risk for muscle weakness in Japanese patients with type 1 diabetes . J Diabetes Investig . 2017 ; 8 ( 3 ): 377 – 382 . Crossref PubMed Google Scholar

17. Yang C , Li C , Liu C , et al. Relationship among urinary advanced glycation‐end products, skeletal muscle mass and physical performance in community‐dwelling older adults . Geriatr Gerontol Int . 2019 ; 19 ( 10 ): 1017 – 1022 . Crossref PubMed Google Scholar

18. Kato M , Kubo A , Sugioka Y , et al. Relationship between advanced glycation end‐product accumulation and low skeletal muscle mass in Japanese men and women . Geriatr Gerontol Int . 2017 ; 17 ( 5 ): 785 – 790 . Crossref PubMed Google Scholar

19. Snow LM , Fugere NA , Thompson LV . Advanced glycation end-product accumulation and associated protein modification in type II skeletal muscle with aging . J Gerontol A Biol Sci Med Sci . 2007 ; 62 ( 11 ): 1204 – 1210 . Crossref PubMed Google Scholar

20. Egawa T , Hayashi T . Association of glycative stress with motor and muscle function . Front Physiol . 2022 ; 13 : 855358 . Crossref PubMed Google Scholar

21. Haus JM , Carrithers JA , Trappe SW , Trappe TA . Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle . J Appl Physiol (1985) . 2007 ; 103 ( 6 ): 2068 – 2076 . Crossref PubMed Google Scholar

22. Van Puyvelde K , Mets T , Njemini R , Beyer I , Bautmans I . Effect of advanced glycation end product intake on inflammation and aging: a systematic review . Nutr Rev . 2014 ; 72 ( 10 ): 638 – 650 . Crossref PubMed Google Scholar

23. Twarda-Clapa A , Olczak A , Białkowska AM , Koziołkiewicz M . Advanced glycation end-products (AGEs): formation, chemistry, classification, receptors, and diseases related to AGEs . Cells . 2022 ; 11 ( 8 ): 1312 . Crossref PubMed Google Scholar

24. Rungratanawanich W , Qu Y , Wang X , Essa MM , Song B-J . Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury . Exp Mol Med . 2021 ; 53 ( 2 ): 168 – 188 . Crossref PubMed Google Scholar

25. Cepas V , Collino M , Mayo JC , Sainz RM . Redox signaling and advanced glycation endproducts (AGEs) in diet-related diseases . Antioxidants (Basel) . 2020 ; 9 ( 2 ): 142 . Crossref PubMed Google Scholar

26. Poulsen MW , Hedegaard RV , Andersen JM , et al. Advanced glycation endproducts in food and their effects on health . Food Chem Toxicol . 2013 ; 60 : 10 – 37 . Crossref PubMed Google Scholar

27. Fournet M , Bonté F , Desmoulière A . Glycation damage: a possible hub for major pathophysiological disorders and aging . Aging Dis . 2018 ; 9 ( 5 ): 880 – 900 . Crossref PubMed Google Scholar

28. He C-P , Chen C , Jiang X-C , et al. The role of AGEs in pathogenesis of cartilage destruction in osteoarthritis . Bone Joint Res . 2022 ; 11 ( 5 ): 292 – 300 . Crossref PubMed Google Scholar

29. Cerami C , Founds H , Nicholl I , et al. Tobacco smoke is a source of toxic reactive glycation products . Proc Natl Acad Sci U S A . 1997 ; 94 ( 25 ): 13915 – 13920 . Crossref PubMed Google Scholar

30. Nie C , Li Y , Qian H , Ying H , Wang L . Advanced glycation end products in food and their effects on intestinal tract . Crit Rev Food Sci Nutr . 2022 ; 62 ( 11 ): 3103 – 3115 . Crossref PubMed Google Scholar

31. Nowotny K , Schröter D , Schreiner M , Grune T . Dietary advanced glycation end products and their relevance for human health . Ageing Res Rev . 2018 ; 47 : 55 – 66 . Crossref PubMed Google Scholar

32. Boyer F , Vidot JB , Dubourg AG , Rondeau P , Essop MF , Bourdon E . Oxidative stress and adipocyte biology: focus on the role of AGEs . Oxid Med Cell Longev . 2015 ; 2015 : 534873 . Crossref PubMed Google Scholar

33. Uribarri J , Cai W , Peppa M , et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging . J Gerontol A Biol Sci Med Sci . 2007 ; 62 ( 4 ): 427 – 433 . Crossref PubMed Google Scholar

34. Payne GW . Effect of inflammation on the aging microcirculation: impact on skeletal muscle blood flow control . Microcirculation . 2006 ; 13 ( 4 ): 343 – 352 . Crossref PubMed Google Scholar

35. Suzuki A , Yabu A , Nakamura H . Advanced glycation end products in musculoskeletal system and disorders . Methods . 2022 ; 203 : 179 – 186 . Crossref PubMed Google Scholar

36. Semba RD , Nicklett EJ , Ferrucci L . Does accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol A Biol Sci Med Sci . 2010 ; 65 ( 9 ): 963 – 975 . Crossref PubMed Google Scholar

37. Yabuuchi J , Ueda S , Yamagishi S-I , et al. Association of advanced glycation end products with sarcopenia and frailty in chronic kidney disease . Sci Rep . 2020 ; 10 ( 1 ): 17647 . Crossref PubMed Google Scholar

38. Neeper M , Schmidt AM , Brett J , et al. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins . J Biol Chem . 1992 ; 267 ( 21 ): 14998 – 15004 . PubMed Google Scholar

39. Halaby DM , Mornon JP . The immunoglobulin superfamily: an insight on its tissular, species, and functional diversity . J Mol Evol . 1998 ; 46 ( 4 ): 389 – 400 . Crossref PubMed Google Scholar

40. Schmidt AM , Yan SD , Yan SF , Stern DM . The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses . J Clin Invest . 2001 ; 108 ( 7 ): 949 – 955 . Crossref PubMed Google Scholar

41. Lukic IK , Humpert PM , Nawroth PP , Bierhaus A . The RAGE pathway: activation and perpetuation in the pathogenesis of diabetic neuropathy . Ann N Y Acad Sci . 2008 ; 1126 : 76 – 80 . Crossref PubMed Google Scholar

42. Volpe CMO , Villar-Delfino PH , Dos Anjos PMF , Nogueira-Machado JA . Cellular death, reactive oxygen species (ROS) and diabetic complications . Cell Death Dis . 2018 ; 9 ( 2 ): 119 . Crossref PubMed Google Scholar

43. Neviere R , Yu Y , Wang L , Tessier F , Boulanger E . Implication of advanced glycation end products (Ages) and their receptor (Rage) on myocardial contractile and mitochondrial functions . Glycoconj J . 2016 ; 33 ( 4 ): 607 – 617 . Crossref PubMed Google Scholar

44. Miyazaki A , Nakayama H , Horiuchi S . Scavenger receptors that recognize advanced glycation end products . Trends Cardiovasc Med . 2002 ; 12 ( 6 ): 258 – 262 . Crossref PubMed Google Scholar

45. Ott C , Jacobs K , Haucke E , Navarrete Santos A , Grune T , Simm A . Role of advanced glycation end products in cellular signaling . Redox Biol . 2014 ; 2 : 411 – 429 . Crossref PubMed Google Scholar

46. Cai W , He JC , Zhu L , Chen X , Striker GE , Vlassara H . AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation . Am J Physiol Cell Physiol . 2008 ; 294 ( 1 ): C145 – 52 . Crossref PubMed Google Scholar

47. Cai W , He JC , Zhu L , Lu C , Vlassara H . Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor . Proc Natl Acad Sci U S A . 2006 ; 103 ( 37 ): 13801 – 13806 . Crossref PubMed Google Scholar

48. Lu C , He JC , Cai W , Liu H , Zhu L , Vlassara H . Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells . Proc Natl Acad Sci U S A . 2004 ; 101 ( 32 ): 11767 – 11772 . Crossref PubMed Google Scholar

49. Mastrocola R , Nigro D , Chiazza F , et al. Fructose-derived advanced glycation end-products drive lipogenesis and skeletal muscle reprogramming via SREBP-1c dysregulation in mice . Free Radic Biol Med . 2016 ; 91 : 224 – 235 . Crossref PubMed Google Scholar

50. Yin L , Li N , Jia W , et al. Skeletal muscle atrophy: from mechanisms to treatments . Pharmacol Res . 2021 ; 172 : 105807 . Crossref PubMed Google Scholar

51. Sharples AP , Hughes DC , Deane CS , Saini A , Selman C , Stewart CE . Longevity and skeletal muscle mass: the role of IGF signalling, the sirtuins, dietary restriction and protein intake . Aging Cell . 2015 ; 14 ( 4 ): 511 – 523 . Crossref PubMed Google Scholar

52. Shen Y , Zhang Q , Huang Z , et al. Isoquercitrin delays denervated soleus muscle atrophy by inhibiting oxidative stress and inflammation . Front Physiol . 2020 ; 11 : 988 . Crossref PubMed Google Scholar

53. Park J , Cho J , Song EJ . Ubiquitin-proteasome system (UPS) as a target for anticancer treatment . Arch Pharm Res . 2020 ; 43 ( 11 ): 1144 – 1161 . Crossref PubMed Google Scholar

54. Lee JH , Jeon JH , Lee MJ . Docosahexaenoic acid, a potential treatment for sarcopenia, modulates the ubiquitin–proteasome and the autophagy–lysosome systems . Nutrients . 2020 ; 12 ( 9 ): 2597 . Crossref PubMed Google Scholar

55. Chemello F , Bean C , Cancellara P , Laveder P , Reggiani C , Lanfranchi G . Microgenomic analysis in skeletal muscle: expression signatures of individual fast and slow myofibers . PLoS One . 2011 ; 6 ( 2 ): e16807 . Crossref PubMed Google Scholar

56. Egawa T , Ohno Y , Yokoyama S , et al. The effect of advanced glycation end products on cellular signaling molecules in skeletal muscle . JPFSM . 2018 ; 7 ( 4 ): 229 – 238 . Crossref Google Scholar

57. Chiu C-Y , Yang R-S , Sheu M-L , et al. Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated, AMPK-down-regulated, Akt pathway . J Pathol . 2016 ; 238 ( 3 ): 470 – 482 . Crossref PubMed Google Scholar

58. Lokireddy S , Mouly V , Butler-Browne G , et al. Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins . Am J Physiol Cell Physiol . 2011 ; 301 ( 6 ): C1316 – 24 . Crossref PubMed Google Scholar

59. Jaitovich A , Angulo M , Lecuona E , et al. High CO2 levels cause skeletal muscle atrophy via AMP-activated kinase (AMPK), FoxO3a protein, and muscle-specific Ring finger protein 1 (MuRF1) . J Biol Chem . 2015 ; 290 ( 14 ): 9183 – 9194 . Crossref PubMed Google Scholar

60. Boden G . Obesity, insulin resistance and free fatty acids . Curr Opin Endocrinol Diabetes Obes . 2011 ; 18 ( 2 ): 139 – 143 . Crossref PubMed Google Scholar

61. Samuel VT , Shulman GI . Mechanisms for insulin resistance: common threads and missing links . Cell . 2012 ; 148 ( 5 ): 852 – 871 . Crossref PubMed Google Scholar

62. Yanase T , Yanagita I , Muta K , Nawata H . Frailty in elderly diabetes patients . Endocr J . 2018 ; 65 ( 1 ): 1 – 11 . Crossref PubMed Google Scholar

63. Cassese A , Esposito I , Fiory F , et al. In skeletal muscle advanced glycation end products (AGEs) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for AGEs . J Biol Chem . 2008 ; 283 ( 52 ): 36088 – 36099 . Crossref PubMed Google Scholar

64. Hofmann SM , Dong H-J , Li Z , et al. Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse . Diabetes . 2002 ; 51 ( 7 ): 2082 – 2089 . Crossref PubMed Google Scholar

65. Miele C , Riboulet A , Maitan MA , et al. Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism . J Biol Chem . 2003 ; 278 ( 48 ): 47376 – 47387 . Crossref PubMed Google Scholar

66. Aftab MF , Afridi SK , Ghaffar S , et al. A bis-Schiff base of isatin improves methylglyoxal mediated insulin resistance in skeletal muscle cells . Arch Pharm Res . 2015 . Crossref PubMed Google Scholar

67. Arnold P , Njemini R , Vantieghem S , et al. Reaction time in healthy elderly is associated with chronic low-grade inflammation and advanced glycation end product . Exp Gerontol . 2018 ; 108 : 118 – 124 . Crossref PubMed Google Scholar

68. Hofmann MA , Drury S , Fu C , et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides . Cell . 1999 ; 97 ( 7 ): 889 – 901 . Crossref PubMed Google Scholar

69. Garay-Sevilla ME , Beeri MS , de la Maza MP , Rojas A , Salazar-Villanea S , Uribarri J . The potential role of dietary advanced glycation endproducts in the development of chronic non-infectious diseases: a narrative review . Nutr Res Rev . 2020 ; 33 ( 2 ): 298 – 311 . Crossref PubMed Google Scholar

70. Sun K , Semba RD , Fried LP , Schaumberg DA , Ferrucci L , Varadhan R . Elevated serum carboxymethyl-lysine, an advanced glycation end product, predicts severe walking disability in older women: the Women’s Health and Aging Study I . J Aging Res . 2012 ; 2012 : 586385 . Crossref PubMed Google Scholar

71. Fang W-Y , Tseng Y-T , Lee T-Y , et al. Triptolide prevents LPS-induced skeletal muscle atrophy via inhibiting NF-κB/TNF-α and regulating protein synthesis/degradation pathway . Br J Pharmacol . 2021 ; 178 ( 15 ): 2998 – 3016 . Crossref PubMed Google Scholar

72. Zhang L , Rajan V , Lin E , et al. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease . FASEB J . 2011 ; 25 ( 5 ): 1653 – 1663 . Crossref PubMed Google Scholar

73. Shoelson SE , Lee J , Goldfine AB . Inflammation and insulin resistance . J Clin Invest . 2006 ; 116 ( 7 ): 1793 – 1801 . Crossref PubMed Google Scholar

74. Wang XH , Mitch WE . Muscle wasting from kidney failure-a model for catabolic conditions . Int J Biochem Cell Biol . 2013 ; 45 ( 10 ): 2230 – 2238 . Crossref PubMed Google Scholar

75. Roubenoff R , Parise H , Payette HA , et al. Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study . Am J Med . 2003 ; 115 ( 6 ): 429 – 435 . Crossref PubMed Google Scholar

76. Riuzzi F , Sorci G , Sagheddu R , Chiappalupi S , Salvadori L , Donato R . RAGE in the pathophysiology of skeletal muscle . J Cachexia Sarcopenia Muscle . 2018 ; 9 ( 7 ): 1213 – 1234 . Crossref PubMed Google Scholar

77. Latres E , Amini AR , Amini AA , et al. Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway . J Biol Chem . 2005 ; 280 ( 4 ): 2737 – 2744 . Crossref PubMed Google Scholar

78. Cohen S , Brault JJ , Gygi SP , et al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation . J Cell Biol . 2009 ; 185 ( 6 ): 1083 – 1095 . Crossref PubMed Google Scholar

79. Milan G , Romanello V , Pescatore F , et al. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy . Nat Commun . 2015 ; 6 : 6670 . Crossref PubMed Google Scholar

80. Flisinski M , Brymora A , Elminowska-Wenda G , et al. Morphometric analysis of muscle fibre types in rat locomotor and postural skeletal muscles in different stages of chronic kidney disease . J Physiol Pharmacol . 2014 ; 65 ( 4 ): 567 – 576 . PubMed Google Scholar

81. Martin AI , Nieto-Bona MP , Castillero E , et al. Effect of cyclooxygenase-2 inhibition by meloxicam, on atrogin-1 and myogenic regulatory factors in skeletal muscle of rats injected with endotoxin . J Physiol Pharmacol . 2012 ; 63 ( 6 ): 649 – 659 . PubMed Google Scholar

82. de la Maza MP , Uribarri J , Olivares D , et al. Weight increase is associated with skeletal muscle immunostaining for advanced glycation end products, receptor for advanced glycation end products, and oxidation injury . Rejuvenation Res . 2008 ; 11 ( 6 ): 1041 – 1048 . Crossref PubMed Google Scholar

83. Omura T , Araki A . Skeletal muscle as a treatment target for older adults with diabetes mellitus: the importance of a multimodal intervention based on functional category . Geriatr Gerontol Int . 2022 ; 22 ( 2 ): 110 – 120 . Crossref PubMed Google Scholar

84. Dai D-F , Chiao YA , Marcinek DJ , Szeto HH , Rabinovitch PS . Mitochondrial oxidative stress in aging and healthspan . Longev Healthspan . 2014 ; 3 ( 1 ): 6 . Crossref PubMed Google Scholar

85. Liguori I , Russo G , Curcio F , et al. Oxidative stress, aging, and diseases . Clin Interv Aging . 2018 ; 13 : 757 – 772 . Crossref PubMed Google Scholar

86. Baumann CW , Kwak D , Liu HM , Thompson LV . Age-induced oxidative stress: how does it influence skeletal muscle quantity and quality? J Appl Physiol (1985) . 2016 ; 121 ( 5 ): 1047 – 1052 . Crossref PubMed Google Scholar

87. Kang Q , Yang C . Oxidative stress and diabetic retinopathy: molecular mechanisms, pathogenetic role and therapeutic implications . Redox Biol . 2020 ; 37 : 101799 . Crossref PubMed Google Scholar

88. Livnat-Levanon N , Glickman MH . Ubiquitin-proteasome system and mitochondria - reciprocity . Biochim Biophys Acta . 2011 ; 1809 ( 2 ): 80 – 87 . Crossref PubMed Google Scholar

89. Roy B . Biomolecular basis of the role of diabetes mellitus in osteoporosis and bone fractures . World J Diabetes . 2013 ; 4 ( 4 ): 101 – 113 . Crossref PubMed Google Scholar

90. Ighodaro OM . Molecular pathways associated with oxidative stress in diabetes mellitus . Biomed Pharmacother . 2018 ; 108 : 656 – 662 . Crossref PubMed Google Scholar

91. Inoguchi T , Li P , Umeda F , et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells . Diabetes . 2000 ; 49 ( 11 ): 1939 – 1945 . Crossref PubMed Google Scholar

92. Cai W , Ramdas M , Zhu L , Chen X , Striker GE , Vlassara H . Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1 . Proc Natl Acad Sci U S A . 2012 ; 109 ( 39 ): 15888 – 15893 . Crossref PubMed Google Scholar

93. Yu Y , Wang L , Delguste F , et al. Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway . Free Radic Biol Med . 2017 ; 112 : 397 – 410 . Crossref PubMed Google Scholar

94. Sifuentes-Franco S , Pacheco-Moisés FP , Rodríguez-Carrizalez AD , Miranda-Díaz AG . The role of oxidative stress, mitochondrial function, and autophagy in diabetic polyneuropathy . J Diabetes Res . 2017 ; 2017 : 1673081 . Crossref PubMed Google Scholar

95. Brookes PS , Yoon Y , Robotham JL , Anders MW , Sheu S-S . Calcium, ATP, and ROS: a mitochondrial love-hate triangle . Am J Physiol Cell Physiol . 2004 ; 287 ( 4 ): C817 – 33 . Crossref PubMed Google Scholar

96. Dozio E , Vettoretti S , Lungarella G , Messa P , Corsi Romanelli MM . Sarcopenia in chronic kidney disease: focus on advanced glycation end products as mediators and markers of oxidative stress . Biomedicines . 2021 ; 9 ( 4 ): 405 . Crossref PubMed Google Scholar

97. Popov L-D . Mitochondrial biogenesis: an update . J Cell Mol Med . 2020 ; 24 ( 9 ): 4892 – 4899 . Crossref PubMed Google Scholar

98. Safdar A , Hamadeh MJ , Kaczor JJ , Raha S , Debeer J , Tarnopolsky MA . Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults . PLoS One . 2010 ; 5 ( 5 ): e10778 . Crossref PubMed Google Scholar

99. Tamaki M , Miyashita K , Wakino S , Mitsuishi M , Hayashi K , Itoh H . Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase . Kidney Int . 2014 ; 85 ( 6 ): 1330 – 1339 . Crossref PubMed Google Scholar

100. Monnier VM , Kohn RR , Cerami A . Accelerated age-related browning of human collagen in diabetes mellitus . Proc Natl Acad Sci USA . 1984 ; 81 ( 2 ): 583 – 587 . Crossref PubMed Google Scholar

101. Sell DR , Monnier VM . Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process . J Biol Chem . 1989 ; 264 ( 36 ): 21597 – 21602 . PubMed Google Scholar

102. Dalle-Donne I , Milzani A , Giustarini D , Di Simplicio P , Colombo R , Rossi R . S-NO-actin: S-nitrosylation kinetics and the effect on isolated vascular smooth muscle . J Muscle Res Cell Motil . 2000 ; 21 ( 2 ): 171 – 181 . Crossref PubMed Google Scholar

103. Milzani A , Rossi R , Di Simplicio P , Giustarini D , Colombo R , DalleDonne I . The oxidation produced by hydrogen peroxide on Ca-ATP-G-actin . Protein Sci . 2000 ; 9 ( 9 ): 1774 – 1782 . Crossref PubMed Google Scholar

104. Ramamurthy B , Jones AD , Larsson L . Glutathione reverses early effects of glycation on myosin function . Am J Physiol Cell Physiol . 2003 ; 285 ( 2 ): C419 – 24 . Crossref PubMed Google Scholar

105. Syrový I , Hodný Z . Non-enzymatic glycosylation of myosin: effects of diabetes and ageing . Gen Physiol Biophys . 1992 ; 11 ( 3 ): 301 – 307 . PubMed Google Scholar

106. Uribarri J , Cai W , Ramdas M , et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1 . Diabetes Care . 2011 ; 34 ( 7 ): 1610 – 1616 . Crossref PubMed Google Scholar

107. Dessalle K , Euthine V , Chanon S , et al. SREBP-1 transcription factors regulate skeletal muscle cell size by controlling protein synthesis through myogenic regulatory factors . PLoS One . 2012 ; 7 ( 11 ): e50878 . Crossref PubMed Google Scholar

108. Olguin HC , Olwin BB . Pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: a potential mechanism for self-renewal . Dev Biol . 2004 ; 275 ( 2 ): 375 – 388 . Crossref PubMed Google Scholar

109. Hernández-Hernández JM , García-González EG , Brun CE , Rudnicki MA . The myogenic regulatory factors, determinants of muscle development, cell identity and regeneration . Semin Cell Dev Biol . 2017 ; 72 : 10 – 18 . Crossref PubMed Google Scholar

110. Zammit PS . Function of the myogenic regulatory factors Myf5, MyoD, Myogenin and MRF4 in skeletal muscle, satellite cells and regenerative myogenesis . Semin Cell Dev Biol . 2017 ; 72 : 19 – 32 . Crossref PubMed Google Scholar

111. Riuzzi F , Sorci G , Beccafico S , Donato R . S100B engages RAGE or bFGF/FGFR1 in myoblasts depending on its own concentration and myoblast density. Implications for muscle regeneration . PLoS One . 2012 ; 7 ( 1 ): e28700 . Crossref PubMed Google Scholar

112. Riuzzi F , Sorci G , Sagheddu R , Donato R . HMGB1-RAGE regulates muscle satellite cell homeostasis through p38-MAPK- and myogenin-dependent repression of Pax7 transcription . J Cell Sci . 2012 ; 125 ( Pt 6 ): 1440 – 1454 . Crossref PubMed Google Scholar

113. Takata T , Sakasai-Sakai A , Takeuchi M . Impact of intracellular toxic advanced glycation end-products (TAGE) on murine myoblast cell death . Diabetol Metab Syndr . 2020 ; 12 ( 1 ): 54 . Crossref PubMed Google Scholar

114. Adachi N , Kanazawa I , Tanaka K-I , et al. Insulin-like growth factor-i protects against the detrimental effects of advanced glycation end products and high glucose in myoblastic C2C12 cells . Calcif Tissue Int . 2019 ; 105 ( 1 ): 89 – 96 . Crossref PubMed Google Scholar

115. Tanaka K , Kanazawa I , Yamaguchi T , Yano S , Kaji H , Sugimoto T . Active vitamin D possesses beneficial effects on the interaction between muscle and bone . Biochem Biophys Res Commun . 2014 ; 450 ( 1 ): 482 – 487 . Crossref PubMed Google Scholar

116. Kume S , Kato S , Yamagishi S , et al. Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone . J Bone Miner Res . 2005 ; 20 ( 9 ): 1647 – 1658 . Crossref PubMed Google Scholar

117. Price FD , von Maltzahn J , Bentzinger CF , et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function . Nat Med . 2014 ; 20 ( 10 ): 1174 – 1181 . Crossref PubMed Google Scholar

118. Zetser A , Gredinger E , Bengal E . p38 mitogen-activated protein kinase pathway promotes skeletal muscle differentiation. Participation of the Mef2c transcription factor . J Biol Chem . 1999 ; 274 ( 8 ): 5193 – 5200 . Crossref PubMed Google Scholar

119. Wu Z , Woodring PJ , Bhakta KS , et al. p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps . Mol Cell Biol . 2000 ; 20 ( 11 ): 3951 – 3964 . Crossref PubMed Google Scholar

120. Gillies AR , Lieber RL . Structure and function of the skeletal muscle extracellular matrix . Muscle Nerve . 2011 ; 44 ( 3 ): 318 – 331 . Crossref PubMed Google Scholar

121. Gosselin LE , Adams C , Cotter TA , McCormick RJ , Thomas DP . Effect of exercise training on passive stiffness in locomotor skeletal muscle: role of extracellular matrix . J Appl Physiol (1985) . 1998 ; 85 ( 3 ): 1011 – 1016 . Crossref PubMed Google Scholar

122. Svensson RB , Smith ST , Moyer PJ , Magnusson SP . Effects of maturation and advanced glycation on tensile mechanics of collagen fibrils from rat tail and Achilles tendons . Acta Biomater . 2018 ; 70 : 270 – 280 . Crossref PubMed Google Scholar

123. Olson LC , Redden JT , Schwartz Z , Cohen DJ , McClure MJ . Advanced glycation end-products in skeletal muscle aging . Bioengineering (Basel) . 2021 ; 8 ( 11 ): 168 . Crossref PubMed Google Scholar

124. Howard AC , McNeil AK , Xiong F , Xiong W-C , McNeil PL . A novel cellular defect in diabetes: membrane repair failure . Diabetes . 2011 ; 60 ( 11 ): 3034 – 3043 . Crossref PubMed Google Scholar

125. Hein G , Franke S . Are advanced glycation end-product-modified proteins of pathogenetic importance in fibromyalgia? Rheumatology (Oxford) . 2002 ; 41 ( 10 ): 1163 – 1167 . Crossref PubMed Google Scholar

126. Abate M , Schiavone C , Salini V , Andia I . Management of limited joint mobility in diabetic patients . Diabetes Metab Syndr Obes . 2013 ; 6 : 197 – 207 . Crossref PubMed Google Scholar

127. Alnaqeeb MA , Al Zaid NS , Goldspink G . Connective tissue changes and physical properties of developing and ageing skeletal muscle . J Anat . 1984 ; 139 (Pt 4) ( Pt 4 ): 677 – 689 . PubMed Google Scholar

128. Bartling B , Desole M , Rohrbach S , Silber R-E , Simm A . Age-associated changes of extracellular matrix collagen impair lung cancer cell migration . FASEB J . 2009 ; 23 ( 5 ): 1510 – 1520 . Crossref PubMed Google Scholar

129. Cannata F , Vadalà G , Ambrosio L , et al. The impact of type 2 diabetes on the development of tendinopathy . Diabetes Metab Res Rev . 2021 ; 37 ( 6 ): e3417 . Crossref PubMed Google Scholar

130. Maessen MFH , Schalkwijk CG , Verheggen RJHM , Aengevaeren VL , Hopman MTE , Eijsvogels TMH . A comparison of dicarbonyl stress and advanced glycation endproducts in lifelong endurance athletes vs. sedentary controls . J Sci Med Sport . 2017 ; 20 ( 10 ): 921 – 926 . Crossref PubMed Google Scholar

131. Miller BF , Olesen JL , Hansen M , et al. Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise . J Physiol . 2005 ; 567 ( Pt 3 ): 1021 – 1033 . Crossref PubMed Google Scholar

132. Hepple RT , Rice CL . Innervation and neuromuscular control in ageing skeletal muscle . J Physiol . 2016 ; 594 ( 8 ): 1965 – 1978 . Crossref PubMed Google Scholar

133. Federoff HJ , Lawrence D , Brownlee M . Nonenzymatic glycosylation of laminin and the laminin peptide CIKVAVS inhibits neurite outgrowth . Diabetes . 1993 ; 42 ( 4 ): 509 – 513 . Crossref PubMed Google Scholar

134. Muona P , Peltonen J , Jaakkola S , Uitto J . Increased matrix gene expression by glucose in rat neural connective tissue cells in culture . Diabetes . 1991 ; 40 ( 5 ): 605 – 611 . Crossref PubMed Google Scholar

135. Muona P , Jaakkola S , Zhang RZ , et al. Hyperglycemic glucose concentrations up-regulate the expression of type VI collagen in vitro. Relevance to alterations of peripheral nerves in diabetes mellitus . Am J Pathol . 1993 ; 142 ( 5 ): 1586 – 1597 . PubMed Google Scholar

136. Yasuda H , Terada M , Maeda K , et al. Diabetic neuropathy and nerve regeneration . Prog Neurobiol . 2003 ; 69 ( 4 ): 229 – 285 . Crossref PubMed Google Scholar

137. Xu S , Bao W , Men X , et al. Interleukin-10 protects Schwann cells against advanced glycation end products-induced apoptosis via NF-κB suppression . Exp Clin Endocrinol Diabetes . 2020 ; 128 ( 2 ): 89 – 96 . Crossref PubMed Google Scholar

138. Fukunaga M , Miyata S , Liu BF , et al. Methylglyoxal induces apoptosis through activation of p38 MAPK in rat Schwann cells . Biochem Biophys Res Commun . 2004 ; 320 ( 3 ): 689 – 695 . Crossref PubMed Google Scholar

139. Fonseca LF , Araújo AB , Quadros KRDS , et al. AGEs accumulation is related to muscle degeneration and vascular calcification in peritoneal dialysis patients . J Bras Nefrol . 2021 ; 43 ( 2 ): 191 – 199 . Crossref PubMed Google Scholar

140. Wang Z-Q , Jing L , Yan J-C , et al. Role of AGEs in the progression and regression of atherosclerotic plaques . Glycoconj J . 2018 ; 35 ( 5 ): 443 – 450 . Crossref PubMed Google Scholar

141. Koike S , Yano S , Tanaka S , Sheikh AM , Nagai A , Sugimoto T . Advanced glycation end-products induce apoptosis of vascular smooth muscle cells: a mechanism for vascular calcification . Int J Mol Sci . 2016 ; 17 ( 9 ): 1567 . Crossref PubMed Google Scholar

142. Otero K , Martínez F , Beltrán A , et al. Albumin-derived advanced glycation end-products trigger the disruption of the vascular endothelial cadherin complex in cultured human and murine endothelial cells . Biochem J . 2001 ; 359 ( Pt 3 ): 567 – 574 . Crossref PubMed Google Scholar

143. Gulino D , Delachanal E , Concord E , et al. Alteration of endothelial cell monolayer integrity triggers resynthesis of vascular endothelium cadherin . J Biol Chem . 1998 ; 273 ( 45 ): 29786 – 29793 . Crossref PubMed Google Scholar

144. Kouidi E , Albani M , Natsis K , et al. The effects of exercise training on muscle atrophy in haemodialysis patients . Nephrol Dial Transplant . 1998 ; 13 ( 3 ): 685 – 699 . Crossref PubMed Google Scholar

145. Ando R , Ueda S , Yamagishi S , et al. Involvement of advanced glycation end product-induced asymmetric dimethylarginine generation in endothelial dysfunction . Diab Vasc Dis Res . 2013 ; 10 ( 5 ): 436 – 441 . Crossref PubMed Google Scholar

146. Uribarri J , del Castillo MD , de la Maza MP , et al. Dietary advanced glycation end products and their role in health and disease . Adv Nutr . 2015 ; 6 ( 4 ): 461 – 473 . Crossref PubMed Google Scholar

147. Galasko D , Bell J , Mancuso JY , et al. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease . Neurology . 2014 ; 82 ( 17 ): 1536 – 1542 . Crossref PubMed Google Scholar

148. Deane R , Singh I , Sagare AP , et al. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease . J Clin Invest . 2012 ; 122 ( 4 ): 1377 – 1392 . Crossref PubMed Google Scholar

149. Gu Q , Wang B , Zhang X-F , Ma Y-P , Liu J-D , Wang X-Z . Contribution of receptor for advanced glycation end products to vasculature-protecting effects of exercise training in aged rats . Eur J Pharmacol . 2014 ; 741 : 186 – 194 . Crossref PubMed Google Scholar

150. Radom-Aizik S , Hayek S , Shahar I , Rechavi G , Kaminski N , Ben-Dov I . Effects of aerobic training on gene expression in skeletal muscle of elderly men . Med Sci Sports Exerc . 2005 ; 37 ( 10 ): 1680 – 1696 . Crossref PubMed Google Scholar

151. Bowen TS , Schuler G , Adams V . Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training . J Cachexia Sarcopenia Muscle . 2015 ; 6 ( 3 ): 197 – 207 . Crossref PubMed Google Scholar

Author contributions

Z. Guo: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

H. Li: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

S. Jiang: Formal analysis, Investigation, Validation, Writing – review & editing

M. Rahmati: Formal analysis, Investigation, Validation, Writing – review & editing

J. Su: Formal analysis, Investigation, Validation, Writing – review & editing

S. Yang: Formal analysis, Investigation, Validation, Writing – review & editing

Y. Wu: Formal analysis, Investigation, Validation, Writing – review & editing

Y. Li: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing

Z. Deng: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing, Data curation, Formal analysis, Investigation, Software, Validation, Visualization

Funding statement

The authors disclose receipt of the following financial or material support for the research, authorship, and/or publication of this article: this work was supported by: National Key R&D Program of China (No. 2023YFC3603400), reported by Y. Li; National Natural Science Foundation of China (No.82472522, 82472495, 92268115, 82071970, 81971775), reported by Y. Wu and Y. Li; National Clinical Research Center for Geriatric Disorders (Xiangya Hospital, No. 2021KF02), reported by Y. Li; Basic Public Welfare Research projects of Wenzhou Science and Technology Bureau (Y20240087), reported by Z. Deng; and Start-up Funding for Talented Scientific Research of the First Affiliated Hospital of Wenzhou Medical University (2023QD026), reported by Z. Deng.

ICMJE COI statement

Y. Li reports funding from National Key R&D Program of China (No. 2023YFC3603400), National Natural Science Foundation of China (No.82472522, 92268115), and National Clinical Research Center for Geriatric Disorders (Xiangya Hospital, No. 2021KF02), related to this study. Y. Wu reports funding from National Natural Science Foundation of China (No.82472495, 82071970, 81971775), related to this study. Z. Deng reports funding from Basic Public Welfare Research projects of Wenzhou Science and Technology Bureau (Y20240087) and Start-up Funding for Talented Scientific Research of the First Affiliated Hospital of Wenzhou Medical University (2023QD026), related to this study.

Data sharing

The data that support the findings for this study are available to other researchers from the corresponding author upon reasonable request.

Acknowledgements

The authors thank the National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University for their support of this work.

Open access funding

The authors report that they received open access funding for their manuscript from the Ministry of Science and Technology of the People's Republic of China, the National Key R&D Program of China (No. 2023YFC3603400).

© 2025 Guo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/

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Information

Journal

Bone & Joint Research

Volume

14 No.3 | Pages 185 - 198

Section

Other

Published

04 March 2025

DOI

Authors

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Zhaojing Guo

Researcher

Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China

Xiangya School of Medicine, Central South University, Changsha, China

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Hengzhen Li

Researcher

Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China

National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

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Shide Jiang

Associate Chief Physician

The Central Hospital of Yongzhou, Yongzhou, China

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Masoud Rahmati

Professor

Department of Physical Education and Sport Sciences, Faculty of Literature and Human Sciences, Lorestan University, Khorramabad, Iran

Department of Physical Education and Sport Sciences, Faculty of Literature and Humanities, Vali-E-Asr University of Rafsanjan, Rafsanjan, Iran

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Jingyue Su

Resident

Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Geriatrics Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

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Shengwu Yang

Chief Physician

Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Geriatrics Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

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Yuxiang Wu

Professor

Department of Health and Physical Education, Jianghan University, Wuhan, China

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Yusheng Li

Professor, Orthopaedic Surgeon

Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China

National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

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Zhenhan Deng

Associate Chief Physician

Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Geriatrics Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

dengzhenhan@wmu.edu.cn

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Supplementary Material

ICMJE forms

Keywords

Sarcopenia

Muscle atrophy

Advanced glycation end-products

AGE cross-linking

AGE-RAGE axis

loss of muscle strength

skeletal muscle

inflammation

lipids

skeletal muscle atrophy

muscle regeneration

lesions

extracellular matrix

vascular disorders

pathogenesis

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Figures

Fig. 1

Formation of advanced glycation end-products (AGEs).

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Fig. 2

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Fig. 3

The pathogenic role of advanced glycation end-products (AGEs) in skeletal muscle. ECM, extracellular matrix; NMJ, neuromuscular junction. Created with BioRender.com, with permission.

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References

1. Find in article

Zhong Q , Zheng K , Li W , et al. Post-translational regulation of muscle growth, muscle aging and sarcopenia . J Cachexia Sarcopenia Muscle . 2023 ; 14 ( 3 ): 1212 – 1227 .

Crossref PubMed Google Scholar

2. Find in article

Sousa-Victor P , García-Prat L , Muñoz-Cánoves P . Control of satellite cell function in muscle regeneration and its disruption in ageing . Nat Rev Mol Cell Biol . 2022 ; 23 ( 3 ): 204 – 226 .

Crossref PubMed Google Scholar

3. Find in article

Mesinovic J , Zengin A , De Courten B , Ebeling PR , Scott D . Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship . Diabetes Metab Syndr Obes . 2019 ; 12 : 1057 – 1072 .

Crossref PubMed Google Scholar

4. Find in article

Larsson L , Degens H , Li M , et al. Sarcopenia: aging-related loss of muscle mass and function . Physiol Rev . 2019 ; 99 ( 1 ): 427 – 511 .

Crossref PubMed Google Scholar

5. Find in article

Anker SD , Morley JE , von Haehling S . Welcome to the ICD-10 code for sarcopenia . J Cachexia Sarcopenia Muscle . 2016 ; 7 ( 5 ): 512 – 514 .

Crossref PubMed Google Scholar

6. Find in article

Cruz-Jentoft AJ , Sayer AA . Sarcopenia . Lancet . 2019 ; 393 ( 10191 ): 2636 – 2646 .

Crossref PubMed Google Scholar

7. Find in article

Ferrucci L , de Cabo R , Knuth ND , Studenski S . Of Greek heroes, wiggling worms, mighty mice, and old body builders . J Gerontol A Biol Sci Med Sci . 2012 ; 67 ( 1 ): 13 – 16 .

Crossref PubMed Google Scholar

8. Find in article

Schiaffino S , Reggiani C . Fiber types in mammalian skeletal muscles . Physiol Rev . 2011 ; 91 ( 4 ): 1447 – 1531 .

Crossref PubMed Google Scholar

9. Find in article

Walston JD . Sarcopenia in older adults . Curr Opin Rheumatol . 2012 ; 24 ( 6 ): 623 – 627 .

Crossref PubMed Google Scholar

10. Find in article

Joanisse S , Nederveen JP , Snijders T , McKay BR , Parise G . Skeletal muscle regeneration, repair and remodelling in aging: the importance of muscle stem cells and vascularization . Gerontology . 2017 ; 63 ( 1 ): 91 – 100 .

Crossref PubMed Google Scholar

11. Find in article

Chen J-H , Lin X , Bu C , Zhang X . Role of advanced glycation end products in mobility and considerations in possible dietary and nutritional intervention strategies . Nutr Metab (Lond) . 2018 ; 15 ( 1 ): 72 .

Crossref PubMed Google Scholar

12. Find in article

Luevano-Contreras C , Chapman-Novakofski K . Dietary advanced glycation end products and aging . Nutrients . 2010 ; 2 ( 12 ): 1247 – 1265 .

Crossref PubMed Google Scholar

13. Find in article

Ahmed N . Advanced glycation endproducts--role in pathology of diabetic complications . Diabetes Res Clin Pract . 2005 ; 67 ( 1 ): 3 – 21 .

Crossref PubMed Google Scholar

14. Find in article

Waqas K , Chen J , Trajanoska K , et al. Skin autofluorescence, a noninvasive biomarker for advanced glycation end-products, is associated with sarcopenia . J Clin Endocrinol Metab . 2022 ; 107 ( 2 ): e793 – e803 .

Crossref PubMed Google Scholar

15. Find in article

Mori H , Kuroda A , Ishizu M , et al. Association of accumulated advanced glycation end-products with a high prevalence of sarcopenia and dynapenia in patients with type 2 diabetes . J Diabetes Investig . 2019 ; 10 ( 5 ): 1332 – 1340 .

Crossref PubMed Google Scholar

16. Find in article

Mori H , Kuroda A , Araki M , et al. Advanced glycation end-products are a risk for muscle weakness in Japanese patients with type 1 diabetes . J Diabetes Investig . 2017 ; 8 ( 3 ): 377 – 382 .

Crossref PubMed Google Scholar

17. Find in article

Yang C , Li C , Liu C , et al. Relationship among urinary advanced glycation‐end products, skeletal muscle mass and physical performance in community‐dwelling older adults . Geriatr Gerontol Int . 2019 ; 19 ( 10 ): 1017 – 1022 .

Crossref PubMed Google Scholar

18. Find in article

Kato M , Kubo A , Sugioka Y , et al. Relationship between advanced glycation end‐product accumulation and low skeletal muscle mass in Japanese men and women . Geriatr Gerontol Int . 2017 ; 17 ( 5 ): 785 – 790 .

Crossref PubMed Google Scholar

19. Find in article

Snow LM , Fugere NA , Thompson LV . Advanced glycation end-product accumulation and associated protein modification in type II skeletal muscle with aging . J Gerontol A Biol Sci Med Sci . 2007 ; 62 ( 11 ): 1204 – 1210 .

Crossref PubMed Google Scholar

20. Find in article

Egawa T , Hayashi T . Association of glycative stress with motor and muscle function . Front Physiol . 2022 ; 13 : 855358 .

Crossref PubMed Google Scholar

21. Find in article

Haus JM , Carrithers JA , Trappe SW , Trappe TA . Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle . J Appl Physiol (1985) . 2007 ; 103 ( 6 ): 2068 – 2076 .

Crossref PubMed Google Scholar

22. Find in article

Van Puyvelde K , Mets T , Njemini R , Beyer I , Bautmans I . Effect of advanced glycation end product intake on inflammation and aging: a systematic review . Nutr Rev . 2014 ; 72 ( 10 ): 638 – 650 .

Crossref PubMed Google Scholar

23. Find in article

Twarda-Clapa A , Olczak A , Białkowska AM , Koziołkiewicz M . Advanced glycation end-products (AGEs): formation, chemistry, classification, receptors, and diseases related to AGEs . Cells . 2022 ; 11 ( 8 ): 1312 .

Crossref PubMed Google Scholar

24. Find in article

Rungratanawanich W , Qu Y , Wang X , Essa MM , Song B-J . Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury . Exp Mol Med . 2021 ; 53 ( 2 ): 168 – 188 .

Crossref PubMed Google Scholar

25. Find in article

Cepas V , Collino M , Mayo JC , Sainz RM . Redox signaling and advanced glycation endproducts (AGEs) in diet-related diseases . Antioxidants (Basel) . 2020 ; 9 ( 2 ): 142 .

Crossref PubMed Google Scholar

26. Find in article

Poulsen MW , Hedegaard RV , Andersen JM , et al. Advanced glycation endproducts in food and their effects on health . Food Chem Toxicol . 2013 ; 60 : 10 – 37 .

Crossref PubMed Google Scholar

27. Find in article

Fournet M , Bonté F , Desmoulière A . Glycation damage: a possible hub for major pathophysiological disorders and aging . Aging Dis . 2018 ; 9 ( 5 ): 880 – 900 .

Crossref PubMed Google Scholar

28. Find in article

He C-P , Chen C , Jiang X-C , et al. The role of AGEs in pathogenesis of cartilage destruction in osteoarthritis . Bone Joint Res . 2022 ; 11 ( 5 ): 292 – 300 .

Crossref PubMed Google Scholar

29. Find in article

Cerami C , Founds H , Nicholl I , et al. Tobacco smoke is a source of toxic reactive glycation products . Proc Natl Acad Sci U S A . 1997 ; 94 ( 25 ): 13915 – 13920 .

Crossref PubMed Google Scholar

30. Find in article

Nie C , Li Y , Qian H , Ying H , Wang L . Advanced glycation end products in food and their effects on intestinal tract . Crit Rev Food Sci Nutr . 2022 ; 62 ( 11 ): 3103 – 3115 .

Crossref PubMed Google Scholar

31. Find in article

Nowotny K , Schröter D , Schreiner M , Grune T . Dietary advanced glycation end products and their relevance for human health . Ageing Res Rev . 2018 ; 47 : 55 – 66 .

Crossref PubMed Google Scholar

32. Find in article

Boyer F , Vidot JB , Dubourg AG , Rondeau P , Essop MF , Bourdon E . Oxidative stress and adipocyte biology: focus on the role of AGEs . Oxid Med Cell Longev . 2015 ; 2015 : 534873 .

Crossref PubMed Google Scholar

33. Find in article

Uribarri J , Cai W , Peppa M , et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging . J Gerontol A Biol Sci Med Sci . 2007 ; 62 ( 4 ): 427 – 433 .

Crossref PubMed Google Scholar

34. Find in article

Payne GW . Effect of inflammation on the aging microcirculation: impact on skeletal muscle blood flow control . Microcirculation . 2006 ; 13 ( 4 ): 343 – 352 .

Crossref PubMed Google Scholar

35. Find in article

Suzuki A , Yabu A , Nakamura H . Advanced glycation end products in musculoskeletal system and disorders . Methods . 2022 ; 203 : 179 – 186 .

Crossref PubMed Google Scholar

36. Find in article

Semba RD , Nicklett EJ , Ferrucci L . Does accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol A Biol Sci Med Sci . 2010 ; 65 ( 9 ): 963 – 975 .

Crossref PubMed Google Scholar

37. Find in article

Yabuuchi J , Ueda S , Yamagishi S-I , et al. Association of advanced glycation end products with sarcopenia and frailty in chronic kidney disease . Sci Rep . 2020 ; 10 ( 1 ): 17647 .

Crossref PubMed Google Scholar

38. Find in article

Neeper M , Schmidt AM , Brett J , et al. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins . J Biol Chem . 1992 ; 267 ( 21 ): 14998 – 15004 .

PubMed Google Scholar

39. Find in article

Halaby DM , Mornon JP . The immunoglobulin superfamily: an insight on its tissular, species, and functional diversity . J Mol Evol . 1998 ; 46 ( 4 ): 389 – 400 .

Crossref PubMed Google Scholar

40. Find in article

Schmidt AM , Yan SD , Yan SF , Stern DM . The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses . J Clin Invest . 2001 ; 108 ( 7 ): 949 – 955 .

Crossref PubMed Google Scholar

41. Find in article

Lukic IK , Humpert PM , Nawroth PP , Bierhaus A . The RAGE pathway: activation and perpetuation in the pathogenesis of diabetic neuropathy . Ann N Y Acad Sci . 2008 ; 1126 : 76 – 80 .

Crossref PubMed Google Scholar

42. Find in article

Volpe CMO , Villar-Delfino PH , Dos Anjos PMF , Nogueira-Machado JA . Cellular death, reactive oxygen species (ROS) and diabetic complications . Cell Death Dis . 2018 ; 9 ( 2 ): 119 .

Crossref PubMed Google Scholar

43. Find in article

Neviere R , Yu Y , Wang L , Tessier F , Boulanger E . Implication of advanced glycation end products (Ages) and their receptor (Rage) on myocardial contractile and mitochondrial functions . Glycoconj J . 2016 ; 33 ( 4 ): 607 – 617 .

Crossref PubMed Google Scholar

44. Find in article

Miyazaki A , Nakayama H , Horiuchi S . Scavenger receptors that recognize advanced glycation end products . Trends Cardiovasc Med . 2002 ; 12 ( 6 ): 258 – 262 .

Crossref PubMed Google Scholar

45. Find in article

Ott C , Jacobs K , Haucke E , Navarrete Santos A , Grune T , Simm A . Role of advanced glycation end products in cellular signaling . Redox Biol . 2014 ; 2 : 411 – 429 .

Crossref PubMed Google Scholar

46. Find in article

Cai W , He JC , Zhu L , Chen X , Striker GE , Vlassara H . AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation . Am J Physiol Cell Physiol . 2008 ; 294 ( 1 ): C145 – 52 .

Crossref PubMed Google Scholar

47. Find in article

Cai W , He JC , Zhu L , Lu C , Vlassara H . Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor . Proc Natl Acad Sci U S A . 2006 ; 103 ( 37 ): 13801 – 13806 .

Crossref PubMed Google Scholar

48. Find in article

Lu C , He JC , Cai W , Liu H , Zhu L , Vlassara H . Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells . Proc Natl Acad Sci U S A . 2004 ; 101 ( 32 ): 11767 – 11772 .

Crossref PubMed Google Scholar

49. Find in article

Mastrocola R , Nigro D , Chiazza F , et al. Fructose-derived advanced glycation end-products drive lipogenesis and skeletal muscle reprogramming via SREBP-1c dysregulation in mice . Free Radic Biol Med . 2016 ; 91 : 224 – 235 .

Crossref PubMed Google Scholar

50. Find in article

Yin L , Li N , Jia W , et al. Skeletal muscle atrophy: from mechanisms to treatments . Pharmacol Res . 2021 ; 172 : 105807 .

Crossref PubMed Google Scholar

51. Find in article

Sharples AP , Hughes DC , Deane CS , Saini A , Selman C , Stewart CE . Longevity and skeletal muscle mass: the role of IGF signalling, the sirtuins, dietary restriction and protein intake . Aging Cell . 2015 ; 14 ( 4 ): 511 – 523 .

Crossref PubMed Google Scholar

52. Find in article

Shen Y , Zhang Q , Huang Z , et al. Isoquercitrin delays denervated soleus muscle atrophy by inhibiting oxidative stress and inflammation . Front Physiol . 2020 ; 11 : 988 .

Crossref PubMed Google Scholar

53. Find in article

Park J , Cho J , Song EJ . Ubiquitin-proteasome system (UPS) as a target for anticancer treatment . Arch Pharm Res . 2020 ; 43 ( 11 ): 1144 – 1161 .

Crossref PubMed Google Scholar

54. Find in article

Lee JH , Jeon JH , Lee MJ . Docosahexaenoic acid, a potential treatment for sarcopenia, modulates the ubiquitin–proteasome and the autophagy–lysosome systems . Nutrients . 2020 ; 12 ( 9 ): 2597 .

Crossref PubMed Google Scholar

55. Find in article

Chemello F , Bean C , Cancellara P , Laveder P , Reggiani C , Lanfranchi G . Microgenomic analysis in skeletal muscle: expression signatures of individual fast and slow myofibers . PLoS One . 2011 ; 6 ( 2 ): e16807 .

Crossref PubMed Google Scholar

56. Find in article

Egawa T , Ohno Y , Yokoyama S , et al. The effect of advanced glycation end products on cellular signaling molecules in skeletal muscle . JPFSM . 2018 ; 7 ( 4 ): 229 – 238 .

Crossref Google Scholar

57. Find in article

Chiu C-Y , Yang R-S , Sheu M-L , et al. Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated, AMPK-down-regulated, Akt pathway . J Pathol . 2016 ; 238 ( 3 ): 470 – 482 .

Crossref PubMed Google Scholar

58. Find in article

Lokireddy S , Mouly V , Butler-Browne G , et al. Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins . Am J Physiol Cell Physiol . 2011 ; 301 ( 6 ): C1316 – 24 .

Crossref PubMed Google Scholar

59. Find in article

Jaitovich A , Angulo M , Lecuona E , et al. High CO2 levels cause skeletal muscle atrophy via AMP-activated kinase (AMPK), FoxO3a protein, and muscle-specific Ring finger protein 1 (MuRF1) . J Biol Chem . 2015 ; 290 ( 14 ): 9183 – 9194 .

Crossref PubMed Google Scholar

60. Find in article

Boden G . Obesity, insulin resistance and free fatty acids . Curr Opin Endocrinol Diabetes Obes . 2011 ; 18 ( 2 ): 139 – 143 .

Crossref PubMed Google Scholar

61. Find in article

Samuel VT , Shulman GI . Mechanisms for insulin resistance: common threads and missing links . Cell . 2012 ; 148 ( 5 ): 852 – 871 .

Crossref PubMed Google Scholar

62. Find in article

Yanase T , Yanagita I , Muta K , Nawata H . Frailty in elderly diabetes patients . Endocr J . 2018 ; 65 ( 1 ): 1 – 11 .

Crossref PubMed Google Scholar

63. Find in article

Cassese A , Esposito I , Fiory F , et al. In skeletal muscle advanced glycation end products (AGEs) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for AGEs . J Biol Chem . 2008 ; 283 ( 52 ): 36088 – 36099 .

Crossref PubMed Google Scholar

64. Find in article

Hofmann SM , Dong H-J , Li Z , et al. Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse . Diabetes . 2002 ; 51 ( 7 ): 2082 – 2089 .

Crossref PubMed Google Scholar

65. Find in article

Miele C , Riboulet A , Maitan MA , et al. Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism . J Biol Chem . 2003 ; 278 ( 48 ): 47376 – 47387 .

Crossref PubMed Google Scholar

66. Find in article

Aftab MF , Afridi SK , Ghaffar S , et al. A bis-Schiff base of isatin improves methylglyoxal mediated insulin resistance in skeletal muscle cells . Arch Pharm Res . 2015 .

Crossref PubMed Google Scholar

67. Find in article

Arnold P , Njemini R , Vantieghem S , et al. Reaction time in healthy elderly is associated with chronic low-grade inflammation and advanced glycation end product . Exp Gerontol . 2018 ; 108 : 118 – 124 .

Crossref PubMed Google Scholar

68. Find in article

Hofmann MA , Drury S , Fu C , et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides . Cell . 1999 ; 97 ( 7 ): 889 – 901 .

Crossref PubMed Google Scholar

69. Find in article

Garay-Sevilla ME , Beeri MS , de la Maza MP , Rojas A , Salazar-Villanea S , Uribarri J . The potential role of dietary advanced glycation endproducts in the development of chronic non-infectious diseases: a narrative review . Nutr Res Rev . 2020 ; 33 ( 2 ): 298 – 311 .

Crossref PubMed Google Scholar

70. Find in article

Sun K , Semba RD , Fried LP , Schaumberg DA , Ferrucci L , Varadhan R . Elevated serum carboxymethyl-lysine, an advanced glycation end product, predicts severe walking disability in older women: the Women’s Health and Aging Study I . J Aging Res . 2012 ; 2012 : 586385 .

Crossref PubMed Google Scholar

71. Find in article

Fang W-Y , Tseng Y-T , Lee T-Y , et al. Triptolide prevents LPS-induced skeletal muscle atrophy via inhibiting NF-κB/TNF-α and regulating protein synthesis/degradation pathway . Br J Pharmacol . 2021 ; 178 ( 15 ): 2998 – 3016 .

Crossref PubMed Google Scholar

72. Find in article

Zhang L , Rajan V , Lin E , et al. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease . FASEB J . 2011 ; 25 ( 5 ): 1653 – 1663 .

Crossref PubMed Google Scholar

73. Find in article

Shoelson SE , Lee J , Goldfine AB . Inflammation and insulin resistance . J Clin Invest . 2006 ; 116 ( 7 ): 1793 – 1801 .

Crossref PubMed Google Scholar

74. Find in article

Wang XH , Mitch WE . Muscle wasting from kidney failure-a model for catabolic conditions . Int J Biochem Cell Biol . 2013 ; 45 ( 10 ): 2230 – 2238 .

Crossref PubMed Google Scholar

75. Find in article

Roubenoff R , Parise H , Payette HA , et al. Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study . Am J Med . 2003 ; 115 ( 6 ): 429 – 435 .

Crossref PubMed Google Scholar

76. Find in article

Riuzzi F , Sorci G , Sagheddu R , Chiappalupi S , Salvadori L , Donato R . RAGE in the pathophysiology of skeletal muscle . J Cachexia Sarcopenia Muscle . 2018 ; 9 ( 7 ): 1213 – 1234 .

Crossref PubMed Google Scholar

77. Find in article

Latres E , Amini AR , Amini AA , et al. Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway . J Biol Chem . 2005 ; 280 ( 4 ): 2737 – 2744 .

Crossref PubMed Google Scholar

78. Find in article

Cohen S , Brault JJ , Gygi SP , et al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation . J Cell Biol . 2009 ; 185 ( 6 ): 1083 – 1095 .

Crossref PubMed Google Scholar

79. Find in article

Milan G , Romanello V , Pescatore F , et al. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy . Nat Commun . 2015 ; 6 : 6670 .

Crossref PubMed Google Scholar

80. Find in article

Flisinski M , Brymora A , Elminowska-Wenda G , et al. Morphometric analysis of muscle fibre types in rat locomotor and postural skeletal muscles in different stages of chronic kidney disease . J Physiol Pharmacol . 2014 ; 65 ( 4 ): 567 – 576 .

PubMed Google Scholar

81. Find in article

Martin AI , Nieto-Bona MP , Castillero E , et al. Effect of cyclooxygenase-2 inhibition by meloxicam, on atrogin-1 and myogenic regulatory factors in skeletal muscle of rats injected with endotoxin . J Physiol Pharmacol . 2012 ; 63 ( 6 ): 649 – 659 .

PubMed Google Scholar

82. Find in article

de la Maza MP , Uribarri J , Olivares D , et al. Weight increase is associated with skeletal muscle immunostaining for advanced glycation end products, receptor for advanced glycation end products, and oxidation injury . Rejuvenation Res . 2008 ; 11 ( 6 ): 1041 – 1048 .

Crossref PubMed Google Scholar

83. Find in article

Omura T , Araki A . Skeletal muscle as a treatment target for older adults with diabetes mellitus: the importance of a multimodal intervention based on functional category . Geriatr Gerontol Int . 2022 ; 22 ( 2 ): 110 – 120 .

Crossref PubMed Google Scholar

84. Find in article

Dai D-F , Chiao YA , Marcinek DJ , Szeto HH , Rabinovitch PS . Mitochondrial oxidative stress in aging and healthspan . Longev Healthspan . 2014 ; 3 ( 1 ): 6 .

Crossref PubMed Google Scholar

85. Find in article

Liguori I , Russo G , Curcio F , et al. Oxidative stress, aging, and diseases . Clin Interv Aging . 2018 ; 13 : 757 – 772 .

Crossref PubMed Google Scholar

86. Find in article

Baumann CW , Kwak D , Liu HM , Thompson LV . Age-induced oxidative stress: how does it influence skeletal muscle quantity and quality? J Appl Physiol (1985) . 2016 ; 121 ( 5 ): 1047 – 1052 .

Crossref PubMed Google Scholar

87. Find in article

Kang Q , Yang C . Oxidative stress and diabetic retinopathy: molecular mechanisms, pathogenetic role and therapeutic implications . Redox Biol . 2020 ; 37 : 101799 .

Crossref PubMed Google Scholar

88. Find in article

Livnat-Levanon N , Glickman MH . Ubiquitin-proteasome system and mitochondria - reciprocity . Biochim Biophys Acta . 2011 ; 1809 ( 2 ): 80 – 87 .

Crossref PubMed Google Scholar

89. Find in article

Roy B . Biomolecular basis of the role of diabetes mellitus in osteoporosis and bone fractures . World J Diabetes . 2013 ; 4 ( 4 ): 101 – 113 .

Crossref PubMed Google Scholar

90. Find in article

Ighodaro OM . Molecular pathways associated with oxidative stress in diabetes mellitus . Biomed Pharmacother . 2018 ; 108 : 656 – 662 .

Crossref PubMed Google Scholar

91. Find in article

Inoguchi T , Li P , Umeda F , et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells . Diabetes . 2000 ; 49 ( 11 ): 1939 – 1945 .

Crossref PubMed Google Scholar

92. Find in article

Cai W , Ramdas M , Zhu L , Chen X , Striker GE , Vlassara H . Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1 . Proc Natl Acad Sci U S A . 2012 ; 109 ( 39 ): 15888 – 15893 .

Crossref PubMed Google Scholar

93. Find in article

Yu Y , Wang L , Delguste F , et al. Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway . Free Radic Biol Med . 2017 ; 112 : 397 – 410 .

Crossref PubMed Google Scholar

94. Find in article

Sifuentes-Franco S , Pacheco-Moisés FP , Rodríguez-Carrizalez AD , Miranda-Díaz AG . The role of oxidative stress, mitochondrial function, and autophagy in diabetic polyneuropathy . J Diabetes Res . 2017 ; 2017 : 1673081 .

Crossref PubMed Google Scholar

95. Find in article

Brookes PS , Yoon Y , Robotham JL , Anders MW , Sheu S-S . Calcium, ATP, and ROS: a mitochondrial love-hate triangle . Am J Physiol Cell Physiol . 2004 ; 287 ( 4 ): C817 – 33 .

Crossref PubMed Google Scholar

96. Find in article

Dozio E , Vettoretti S , Lungarella G , Messa P , Corsi Romanelli MM . Sarcopenia in chronic kidney disease: focus on advanced glycation end products as mediators and markers of oxidative stress . Biomedicines . 2021 ; 9 ( 4 ): 405 .

Crossref PubMed Google Scholar

97. Find in article

Popov L-D . Mitochondrial biogenesis: an update . J Cell Mol Med . 2020 ; 24 ( 9 ): 4892 – 4899 .

Crossref PubMed Google Scholar

98. Find in article

Safdar A , Hamadeh MJ , Kaczor JJ , Raha S , Debeer J , Tarnopolsky MA . Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults . PLoS One . 2010 ; 5 ( 5 ): e10778 .

Crossref PubMed Google Scholar

99. Find in article

Tamaki M , Miyashita K , Wakino S , Mitsuishi M , Hayashi K , Itoh H . Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase . Kidney Int . 2014 ; 85 ( 6 ): 1330 – 1339 .

Crossref PubMed Google Scholar

100. Find in article

Monnier VM , Kohn RR , Cerami A . Accelerated age-related browning of human collagen in diabetes mellitus . Proc Natl Acad Sci USA . 1984 ; 81 ( 2 ): 583 – 587 .

Crossref PubMed Google Scholar

101. Find in article

Sell DR , Monnier VM . Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process . J Biol Chem . 1989 ; 264 ( 36 ): 21597 – 21602 .

PubMed Google Scholar

102. Find in article

Dalle-Donne I , Milzani A , Giustarini D , Di Simplicio P , Colombo R , Rossi R . S-NO-actin: S-nitrosylation kinetics and the effect on isolated vascular smooth muscle . J Muscle Res Cell Motil . 2000 ; 21 ( 2 ): 171 – 181 .

Crossref PubMed Google Scholar

103. Find in article

Milzani A , Rossi R , Di Simplicio P , Giustarini D , Colombo R , DalleDonne I . The oxidation produced by hydrogen peroxide on Ca-ATP-G-actin . Protein Sci . 2000 ; 9 ( 9 ): 1774 – 1782 .

Crossref PubMed Google Scholar

104. Find in article

Ramamurthy B , Jones AD , Larsson L . Glutathione reverses early effects of glycation on myosin function . Am J Physiol Cell Physiol . 2003 ; 285 ( 2 ): C419 – 24 .

Crossref PubMed Google Scholar

105. Find in article

Syrový I , Hodný Z . Non-enzymatic glycosylation of myosin: effects of diabetes and ageing . Gen Physiol Biophys . 1992 ; 11 ( 3 ): 301 – 307 .

PubMed Google Scholar

106. Find in article

Uribarri J , Cai W , Ramdas M , et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1 . Diabetes Care . 2011 ; 34 ( 7 ): 1610 – 1616 .

Crossref PubMed Google Scholar

107. Find in article

Dessalle K , Euthine V , Chanon S , et al. SREBP-1 transcription factors regulate skeletal muscle cell size by controlling protein synthesis through myogenic regulatory factors . PLoS One . 2012 ; 7 ( 11 ): e50878 .

Crossref PubMed Google Scholar

108. Find in article

Olguin HC , Olwin BB . Pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: a potential mechanism for self-renewal . Dev Biol . 2004 ; 275 ( 2 ): 375 – 388 .

Crossref PubMed Google Scholar

109. Find in article

Hernández-Hernández JM , García-González EG , Brun CE , Rudnicki MA . The myogenic regulatory factors, determinants of muscle development, cell identity and regeneration . Semin Cell Dev Biol . 2017 ; 72 : 10 – 18 .

Crossref PubMed Google Scholar

110. Find in article

Zammit PS . Function of the myogenic regulatory factors Myf5, MyoD, Myogenin and MRF4 in skeletal muscle, satellite cells and regenerative myogenesis . Semin Cell Dev Biol . 2017 ; 72 : 19 – 32 .

Crossref PubMed Google Scholar

111. Find in article

Riuzzi F , Sorci G , Beccafico S , Donato R . S100B engages RAGE or bFGF/FGFR1 in myoblasts depending on its own concentration and myoblast density. Implications for muscle regeneration . PLoS One . 2012 ; 7 ( 1 ): e28700 .

Crossref PubMed Google Scholar

112. Find in article

Riuzzi F , Sorci G , Sagheddu R , Donato R . HMGB1-RAGE regulates muscle satellite cell homeostasis through p38-MAPK- and myogenin-dependent repression of Pax7 transcription . J Cell Sci . 2012 ; 125 ( Pt 6 ): 1440 – 1454 .

Crossref PubMed Google Scholar

113. Find in article

Takata T , Sakasai-Sakai A , Takeuchi M . Impact of intracellular toxic advanced glycation end-products (TAGE) on murine myoblast cell death . Diabetol Metab Syndr . 2020 ; 12 ( 1 ): 54 .

Crossref PubMed Google Scholar

114. Find in article

Adachi N , Kanazawa I , Tanaka K-I , et al. Insulin-like growth factor-i protects against the detrimental effects of advanced glycation end products and high glucose in myoblastic C2C12 cells . Calcif Tissue Int . 2019 ; 105 ( 1 ): 89 – 96 .

Crossref PubMed Google Scholar

115. Find in article

Tanaka K , Kanazawa I , Yamaguchi T , Yano S , Kaji H , Sugimoto T . Active vitamin D possesses beneficial effects on the interaction between muscle and bone . Biochem Biophys Res Commun . 2014 ; 450 ( 1 ): 482 – 487 .

Crossref PubMed Google Scholar

116. Find in article

Kume S , Kato S , Yamagishi S , et al. Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone . J Bone Miner Res . 2005 ; 20 ( 9 ): 1647 – 1658 .

Crossref PubMed Google Scholar

117. Find in article

Price FD , von Maltzahn J , Bentzinger CF , et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function . Nat Med . 2014 ; 20 ( 10 ): 1174 – 1181 .

Crossref PubMed Google Scholar

118. Find in article

Zetser A , Gredinger E , Bengal E . p38 mitogen-activated protein kinase pathway promotes skeletal muscle differentiation. Participation of the Mef2c transcription factor . J Biol Chem . 1999 ; 274 ( 8 ): 5193 – 5200 .

Crossref PubMed Google Scholar

119. Find in article

Wu Z , Woodring PJ , Bhakta KS , et al. p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps . Mol Cell Biol . 2000 ; 20 ( 11 ): 3951 – 3964 .

Crossref PubMed Google Scholar

120. Find in article

Gillies AR , Lieber RL . Structure and function of the skeletal muscle extracellular matrix . Muscle Nerve . 2011 ; 44 ( 3 ): 318 – 331 .

Crossref PubMed Google Scholar

121. Find in article

Gosselin LE , Adams C , Cotter TA , McCormick RJ , Thomas DP . Effect of exercise training on passive stiffness in locomotor skeletal muscle: role of extracellular matrix . J Appl Physiol (1985) . 1998 ; 85 ( 3 ): 1011 – 1016 .

Crossref PubMed Google Scholar

122. Find in article

Svensson RB , Smith ST , Moyer PJ , Magnusson SP . Effects of maturation and advanced glycation on tensile mechanics of collagen fibrils from rat tail and Achilles tendons . Acta Biomater . 2018 ; 70 : 270 – 280 .

Crossref PubMed Google Scholar

123. Find in article

Olson LC , Redden JT , Schwartz Z , Cohen DJ , McClure MJ . Advanced glycation end-products in skeletal muscle aging . Bioengineering (Basel) . 2021 ; 8 ( 11 ): 168 .

Crossref PubMed Google Scholar

124. Find in article

Howard AC , McNeil AK , Xiong F , Xiong W-C , McNeil PL . A novel cellular defect in diabetes: membrane repair failure . Diabetes . 2011 ; 60 ( 11 ): 3034 – 3043 .

Crossref PubMed Google Scholar

125. Find in article

Hein G , Franke S . Are advanced glycation end-product-modified proteins of pathogenetic importance in fibromyalgia? Rheumatology (Oxford) . 2002 ; 41 ( 10 ): 1163 – 1167 .

Crossref PubMed Google Scholar

126. Find in article

Abate M , Schiavone C , Salini V , Andia I . Management of limited joint mobility in diabetic patients . Diabetes Metab Syndr Obes . 2013 ; 6 : 197 – 207 .

Crossref PubMed Google Scholar

127. Find in article

Alnaqeeb MA , Al Zaid NS , Goldspink G . Connective tissue changes and physical properties of developing and ageing skeletal muscle . J Anat . 1984 ; 139 (Pt 4) ( Pt 4 ): 677 – 689 .

PubMed Google Scholar

128. Find in article

Bartling B , Desole M , Rohrbach S , Silber R-E , Simm A . Age-associated changes of extracellular matrix collagen impair lung cancer cell migration . FASEB J . 2009 ; 23 ( 5 ): 1510 – 1520 .

Crossref PubMed Google Scholar

129. Find in article

Cannata F , Vadalà G , Ambrosio L , et al. The impact of type 2 diabetes on the development of tendinopathy . Diabetes Metab Res Rev . 2021 ; 37 ( 6 ): e3417 .

Crossref PubMed Google Scholar

130. Find in article

Maessen MFH , Schalkwijk CG , Verheggen RJHM , Aengevaeren VL , Hopman MTE , Eijsvogels TMH . A comparison of dicarbonyl stress and advanced glycation endproducts in lifelong endurance athletes vs. sedentary controls . J Sci Med Sport . 2017 ; 20 ( 10 ): 921 – 926 .

Crossref PubMed Google Scholar

131. Find in article

Miller BF , Olesen JL , Hansen M , et al. Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise . J Physiol . 2005 ; 567 ( Pt 3 ): 1021 – 1033 .

Crossref PubMed Google Scholar

132. Find in article

Hepple RT , Rice CL . Innervation and neuromuscular control in ageing skeletal muscle . J Physiol . 2016 ; 594 ( 8 ): 1965 – 1978 .

Crossref PubMed Google Scholar

133. Find in article

Federoff HJ , Lawrence D , Brownlee M . Nonenzymatic glycosylation of laminin and the laminin peptide CIKVAVS inhibits neurite outgrowth . Diabetes . 1993 ; 42 ( 4 ): 509 – 513 .

Crossref PubMed Google Scholar

134. Find in article

Muona P , Peltonen J , Jaakkola S , Uitto J . Increased matrix gene expression by glucose in rat neural connective tissue cells in culture . Diabetes . 1991 ; 40 ( 5 ): 605 – 611 .

Crossref PubMed Google Scholar

135. Find in article

Muona P , Jaakkola S , Zhang RZ , et al. Hyperglycemic glucose concentrations up-regulate the expression of type VI collagen in vitro. Relevance to alterations of peripheral nerves in diabetes mellitus . Am J Pathol . 1993 ; 142 ( 5 ): 1586 – 1597 .

PubMed Google Scholar

136. Find in article

Yasuda H , Terada M , Maeda K , et al. Diabetic neuropathy and nerve regeneration . Prog Neurobiol . 2003 ; 69 ( 4 ): 229 – 285 .

Crossref PubMed Google Scholar

137. Find in article

Xu S , Bao W , Men X , et al. Interleukin-10 protects Schwann cells against advanced glycation end products-induced apoptosis via NF-κB suppression . Exp Clin Endocrinol Diabetes . 2020 ; 128 ( 2 ): 89 – 96 .

Crossref PubMed Google Scholar

138. Find in article

Fukunaga M , Miyata S , Liu BF , et al. Methylglyoxal induces apoptosis through activation of p38 MAPK in rat Schwann cells . Biochem Biophys Res Commun . 2004 ; 320 ( 3 ): 689 – 695 .

Crossref PubMed Google Scholar

139. Find in article

Fonseca LF , Araújo AB , Quadros KRDS , et al. AGEs accumulation is related to muscle degeneration and vascular calcification in peritoneal dialysis patients . J Bras Nefrol . 2021 ; 43 ( 2 ): 191 – 199 .

Crossref PubMed Google Scholar

140. Find in article

Wang Z-Q , Jing L , Yan J-C , et al. Role of AGEs in the progression and regression of atherosclerotic plaques . Glycoconj J . 2018 ; 35 ( 5 ): 443 – 450 .

Crossref PubMed Google Scholar

141. Find in article

Koike S , Yano S , Tanaka S , Sheikh AM , Nagai A , Sugimoto T . Advanced glycation end-products induce apoptosis of vascular smooth muscle cells: a mechanism for vascular calcification . Int J Mol Sci . 2016 ; 17 ( 9 ): 1567 .

Crossref PubMed Google Scholar

142. Find in article

Otero K , Martínez F , Beltrán A , et al. Albumin-derived advanced glycation end-products trigger the disruption of the vascular endothelial cadherin complex in cultured human and murine endothelial cells . Biochem J . 2001 ; 359 ( Pt 3 ): 567 – 574 .

Crossref PubMed Google Scholar

143. Find in article

Gulino D , Delachanal E , Concord E , et al. Alteration of endothelial cell monolayer integrity triggers resynthesis of vascular endothelium cadherin . J Biol Chem . 1998 ; 273 ( 45 ): 29786 – 29793 .

Crossref PubMed Google Scholar

144. Find in article

Kouidi E , Albani M , Natsis K , et al. The effects of exercise training on muscle atrophy in haemodialysis patients . Nephrol Dial Transplant . 1998 ; 13 ( 3 ): 685 – 699 .

Crossref PubMed Google Scholar

145. Find in article

Ando R , Ueda S , Yamagishi S , et al. Involvement of advanced glycation end product-induced asymmetric dimethylarginine generation in endothelial dysfunction . Diab Vasc Dis Res . 2013 ; 10 ( 5 ): 436 – 441 .

Crossref PubMed Google Scholar

146. Find in article

Uribarri J , del Castillo MD , de la Maza MP , et al. Dietary advanced glycation end products and their role in health and disease . Adv Nutr . 2015 ; 6 ( 4 ): 461 – 473 .

Crossref PubMed Google Scholar

147. Find in article

Galasko D , Bell J , Mancuso JY , et al. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease . Neurology . 2014 ; 82 ( 17 ): 1536 – 1542 .

Crossref PubMed Google Scholar

148. Find in article

Deane R , Singh I , Sagare AP , et al. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease . J Clin Invest . 2012 ; 122 ( 4 ): 1377 – 1392 .

Crossref PubMed Google Scholar

149. Find in article

Gu Q , Wang B , Zhang X-F , Ma Y-P , Liu J-D , Wang X-Z . Contribution of receptor for advanced glycation end products to vasculature-protecting effects of exercise training in aged rats . Eur J Pharmacol . 2014 ; 741 : 186 – 194 .

Crossref PubMed Google Scholar

150. Find in article

Radom-Aizik S , Hayek S , Shahar I , Rechavi G , Kaminski N , Ben-Dov I . Effects of aerobic training on gene expression in skeletal muscle of elderly men . Med Sci Sports Exerc . 2005 ; 37 ( 10 ): 1680 – 1696 .

Crossref PubMed Google Scholar

151. Find in article

Bowen TS , Schuler G , Adams V . Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training . J Cachexia Sarcopenia Muscle . 2015 ; 6 ( 3 ): 197 – 207 .

Crossref PubMed Google Scholar