bioengineering Review Advanced Glycation End-Products in Skeletal Muscle Aging Lucas C. Olson 1,2 , James T. Redden 1 , Zvi Schwartz 1,3 , David J. Cohen 1 and Michael J. McClure 1, *   Citation: Olson, L.C.; Redden, J.T.; Schwartz, Z.; Cohen, D.J.; McClure, M.J. Advanced Glycation End-Products in Skeletal Muscle Aging. Bioengineering 2021, 8, 168. https://doi.org/10.3390/ bioengineering8110168 Academic Editor: Stuart Goodman Received: 30 September 2021 Accepted: 28 October 2021 Published: 1 November 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA; olsonlc@vcu.edu (L.C.O.); reddenjt@vcu.edu (J.T.R.); zschwartz@vcu.edu (Z.S.); djcohen@vcu.edu (D.J.C.) 2 Department of Gerontology, College of Health Professions, Virginia Commonwealth University, Richmond, VA 23298, USA 3 Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA * Correspondence: mccluremj2@vcu.edu 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. Keywords: skeletal muscle aging; sarcopenia; advanced glycation end-products; collagen; collagen cross-linking; motor nerve 1. Introduction Musculoskeletal injury increases due to falls and other accidental injuries in old age, and age-dependent alterations to skeletal muscle structure and function are the primary causal factors of such incidents [1]. The etiology of muscle atrophy due to aging, or sarcopenia, includes loss in muscle strength, muscle fiber wasting, increased intramuscular connective tissue, and a disruption of the muscle stem cell population that results in muscle that is weaker, stiffer, and less able to regenerate [2–8]. Muscular aging is multifactorial, involving extrinsic and intrinsic mechanisms that attack both the cellular components and extracellular matrix (ECM). Advanced glycation end-products (AGEs), the final derivative of the Maillard or browning reaction, are known to accumulate in musculoskeletal tissues in old age and are thought to play a role in the development of sarcopenia [9–12]. AGEs preferentially accrue on the long-lived extracellular matrix (ECM) proteins, especially collagens, since their formation relies on its precursors’ stochastic reaction (glucose and proteins) via the Maillard reaction. In addition to having a long half-life, collagens are rich in repeating arginine and lysine amino acids that potentiate the reaction between collagen and AGE precursors, further predisposing collagen to these glycation cross-links [12]. Non-enzymatic cross-linking by AGEs decrease collagen’s susceptibility to degradation by matrix metalloproteinases, causing the build-up of collagen and subsequent stiffening of the usually pliant skeletal muscle ECM [13]. There are only a handful of reviews that focus on the aging and cross-linking of the sclerotic collagens in skeletal muscle, and even Bioengineering 2021, 8, 168. https://doi.org/10.3390/bioengineering8110168 https://www.mdpi.com/journal/bioengineering