Advanced Glycation End-Products in Skeletal Muscle Aging

Abstract

Advanced age causes skeletal muscle to undergo deleterious changes including muscle atrophy, fast-to-slow muscle fiber transition, and an increase in collagenous material that culminates in the age-dependent muscle wasting disease known as sarcopenia. Advanced glycation end-products (AGEs) non-enzymatically accumulate on the muscular collagens in old age via the Maillard reaction, potentiating the accumulation of intramuscular collagen and stiffening the microenvironment through collagen cross-linking. This review contextualizes known aspects of skeletal muscle extracellular matrix (ECM) aging, especially the role of collagens and AGE cross-linking, and underpins the motor nerve’s role in this aging process. Specific directions for future research are also discussed, with the understudied role of AGEs in skeletal muscle aging highlighted. Despite more than a half century of research, the role that intramuscular collagen aggregation and cross-linking plays in sarcopenia is well accepted yet not well integrated with current knowledge of AGE’s effects on muscle physiology. Furthermore, the possible impact that motor nerve aging has on intramuscular cross-linking and muscular AGE levels is posited.

Metallothionein gene deficiency facilitates the differentiation of C2C12 myoblasts into slow-twitch myotubes

“…Fast-twitch muscles are more sensitive to aging than slow-twitch muscles. Aging triggers a myo ber-type transition from fast-twitch to slow-twitch bers, called the "fast-to-slow muscle transition" (Ohlendieck 2011;Miljkovic et al 2015;Olson et al 2021). The mechanism underlying the fast-to-slow muscle ber transition with aging is still unclear.…”

Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease

“…Canonically, RAGE signaling in skeletal muscle is involved in normal skeletomuscular function and maintenance; however, depending on the ligand, RAGE activation also causes wasting, inflammation, and skeletal muscle aging. ,, These effects are proposed to occur by AGE-mediated aging and cross-linking of critical components of the extracellular matrix such as collagen and the basal lamina. , Collectively, this leaves the individual prone to developing overt skeletomuscular atrophy, sarcopenia, and osteoporosis. , In myoblast cells, MG-AGEs increased oxidative stress and reduced myotube formation while upregulating RAGE expression and activation . In diabetic mice, skeletal muscle and plasma have significantly higher MG-AGEs compared to controls, suggesting a link between MG-AGE production and accumulation in the skeletal muscle .…”

“… 195 , 196 Collectively, this leaves the individual prone to developing overt skeletomuscular atrophy, sarcopenia, and osteoporosis. 193 , 197 In myoblast cells, MG-AGEs increased oxidative stress and reduced myotube formation while upregulating RAGE expression and activation. 198 In diabetic mice, skeletal muscle and plasma have significantly higher MG-AGEs compared to controls, suggesting a link between MG-AGE production and accumulation in the skeletal muscle.…”

Advanced glycation end products in skeletal muscle health and sarcopenia: A systematic review of observational studies

“…Non-enzymatic glycation of proteins and other macromolecules has been recognised as another fundamental molecular mechanism of ageing and chronic diseases (reviewed in Chaudhuri et al, 2018;Gugliucci, 2017;Ramasamy et al, 2005;Reynaert et al, 2016;Rowan et al, 2018;Semba et al, 2010b). The possible involvement of glycation in pathophysiology of musculoskeletal ageing and disease has been discussed in several recent narrative reviews (e.g., Chen et al, 2018;Olson et al, 2021;Riuzzi et al, 2018;Suzuki et al, 2022), including a critical appraisal of the current methodology for detection of AGEs and potential therapeutic strategies (Suzuki et al, 2022). However, a systematic review of evidence from observational studies about the role of glycation in muscle health and sarcopenia is lacking.…”