Introduction: Animal studies suggest that advanced glycation end products (AGEs) and their interaction with receptor for AGEs (RAGE) are involved in sarcopenia, but their relationship in human skeletal muscles has yet to be elucidated. We aimed to determine whether RAGE expression in human skeletal muscle is associated with serum AGE levels and sarcopenia-related changes. Methods: We retrospectively reviewed 33 consecutive women (mean age, 65 years) with distal radius fracture who had consented to donate a sample of forearm muscle for research purposes, which was taken during surgical fracture repair. The muscle RAGE expression was measured with immunohistochemistry staining and serum AGE levels using ELISA method. We compared RAGE expression and AGE levels in patients with and without sarcopenia. We also correlated RAGE expression with such clinical parameters as demographic factors, as well as sarcopenia-related changes, including grip strength, appendicular skeletal muscle mass, and muscle cross-sectional area (CSA) ratios. Results: Twelve patients (36%) were diagnosed with sarcopenia. They had a significantly higher RAGE expression (p = 0.044) and AGE level (p < 0.001) than those without sarcopenia. The RAGE expression correlated significantly with a high AGE level (r = 0.510, p = 0.011) and correlated inversely with a muscle CSA ratio (r = −0.696, p < 0.001). Discussion: This study shows that RAGE expression increases in sarcopenic patient skeletal muscles. This expression also correlates positively with serum AGE levels and inversely with muscle CSA ratios. Further studies are necessary to determine whether targeting RAGEs can be a therapeutic option for sarcopenia.

Keywords:
Sarcopenia, Skeletal muscle, RAGE
1.
Cho MR, Lee S, Song SK. A review of sarcopenia pathophysiology, diagnosis, treatment and future direction. J Korean Med Sci. 2022;37(18):e146.
2.
Doherty TJ. Invited review: aging and sarcopenia. J Appl Physiol. 2003 Oct;95(4):1717–27.
3.
Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019 Jul;48(4):601.
4.
Kim SH, Jeong JB, Kang J, Ahn DW, Kim JW, Kim BG, et al. Association between sarcopenia level and metabolic syndrome. PLoS One. 2021 Mar;16(3):e0248856.
5.
Atlantis E, Martin SA, Haren MT, Taylor AW, Wittert GA; Members of the Florey Adelaide Male Ageing Study. Inverse associations between muscle mass, strength, and the metabolic syndrome. Metabolism. 2009 Jul;58(7):1013–22.
6.
Seo DH, Lee YH, Suh YJ, Ahn SH, Hong S, Choi YJ, et al. Low muscle mass is associated with carotid atherosclerosis in patients with type 2 diabetes. Atherosclerosis. 2020 Jul;305:19–25.
7.
Sanada K, Miyachi M, Tanimoto M, Yamamoto K, Murakami H, Okumura S, et al. A cross-sectional study of sarcopenia in Japanese men and women: reference values and association with cardiovascular risk factors. Eur J Appl Physiol. 2010 Sep;110(1):57–65.
8.
Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R. The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc. 2004 Jan;52(1):80–5.
9.
Gale CR, Martyn CN, Cooper C, Sayer AA. Grip strength, body composition, and mortality. Int J Epidemiol. 2007 Feb;36(1):228–35.
10.
Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001 Feb;44(2):129–46.
11.
Dunn JA, McCance DR, Thorpe SR, Lyons TJ, Baynes JW. Age-dependent accumulation of N epsilon-(carboxymethyl)lysine and N epsilon-(carboxymethyl)hydroxylysine in human skin collagen. Biochemistry. 1991 Feb;30(5):1205–10.
12.
Dunn JA, Patrick JS, Thorpe SR, Baynes JW. Oxidation of glycated proteins: age-dependent accumulation of N epsilon-carboxymethyl)lysine in lens proteins. Biochemistry. 1989 Nov;28(24):9464–8.
13.
Schleicher ED, Wagner E, Nerlich AG. Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest. 1997 Feb;99(3):457–68.
14.
Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens. 2004 Dec;17(12 Pt 2):23S–30S.
15.
Tabara Y, Ikezoe T, Yamanaka M, Setoh K, Segawa H, Kawaguchi T, et al. Advanced glycation end product accumulation is associated with low skeletal muscle mass, weak muscle strength, and reduced bone density: the nagahama study. J Gerontol A Biol Sci Med Sci. 2019 Aug;74(9):1446–53.
16.
Riuzzi F, Sorci G, Sagheddu R, Chiappalupi S, Salvadori L, Donato R. RAGE in the pathophysiology of skeletal muscle. J Cachexia Sarcopenia Muscle. 2018 Dec;9(7):1213–34.
17.
Haslbeck KM, Friess U, Schleicher ED, Bierhaus A, Nawroth PP, Kirchner A, et al. The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy. Acta Neuropathol. 2005 Sep;110(3):247–54.
18.
Chiu CY, Yang RS, Sheu ML, Chan DC, Yang TH, Tsai KS, 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 Feb;238(3):470–82.
19.
Chiappalupi S, Sorci G, Vukasinovic A, Salvadori L, Sagheddu R, Coletti D, et al. Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia. J Cachexia Sarcopenia Muscle. 2020 Aug;11(4):929–46.
20.
Davis HM, Essex AL, Valdez S, Deosthale PJ, Aref MW, Allen MR, et al. Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice. Bone. 2019 Jul;124:89–102.
21.
Dalal M, Ferrucci L, Sun K, Beck J, Fried LP, Semba RD. Elevated serum advanced glycation end products and poor grip strength in older community-dwelling women. J Gerontol A Biol Sci Med Sci. 2009 Jan;64(1):132–7.
22.
Semba RD, Bandinelli S, Sun K, Guralnik JM, Ferrucci L. Relationship of an advanced glycation end product, plasma carboxymethyl-lysine, with slow walking speed in older adults: the InCHIANTI study. Eur J Appl Physiol. 2010 Jan;108(1):191–5.
23.
Drenth H, Zuidema SU, Krijnen WP, Bautmans I, Smit AJ, van der Schans C, et al. Advanced glycation end products are associated with physical activity and physical functioning in the older population. J Gerontol A Biol Sci Med Sci. 2018 Oct;73(11):1545–51.
24.
Mori H, Kuroda A, Araki M, Suzuki R, Taniguchi S, Tamaki M, et al. Advanced glycation end-products are a risk for muscle weakness in Japanese patients with type 1 diabetes. J Diabetes Investig. 2017 May;8(3):377–82.
25.
Kato M, Kubo A, Sugioka Y, Mitsui R, Fukuhara N, Nihei F, et al. Relationship between advanced glycation end-product accumulation and low skeletal muscle mass in Japanese men and women. Geriatr Gerontol Int. 2017 May;17(5):785–90.
26.
Momma H, Niu K, Kobayashi Y, Guan L, Sato M, Guo H, et al. Skin advanced glycation end product accumulation and muscle strength among adult men. Eur J Appl Physiol. 2011 Jul;111(7):1545–52.
27.
Walker RA. Quantification of immunohistochemistry--issues concerning methods, utility and semiquantitative assessment I. Histopathology. 2006;49(4):406–10.
28.
Petersen P, Petrick M, Connor H, Conklin D. Grip strength and hand dominance: challenging the 10% rule. Am J Occup Ther. 1989 Jul;43(7):444–7.
29.
Chen LK, Liu LK, Woo J, Assantachai P, Auyeung TW, Bahyah KS, et al. Sarcopenia in asia: consensus report of the asian working group for sarcopenia. J Am Med Dir Assoc. 2014 Feb;15(2):95–101.
30.
Baumgartner RN, Koehler KM, Gallagher D, Romero L, Heymsfield SB, Ross RR, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol. 1998 Apr;147(8):755–63.
31.
Ceglia L, Niramitmahapanya S, Price LL, Harris SS, Fielding RA, Dawson-Hughes B. An evaluation of the reliability of muscle fiber cross-sectional area and fiber number measurements in rat skeletal muscle. Biol Proced Online. 2013 Mar;15(1):6.
32.
Mattiello-Sverzut AC, Petersen SG, Kjaer M, Mackey AL. Morphological adaptation of muscle collagen and receptor of advanced glycation end product (RAGE) in osteoarthritis patients with 12 weeks of resistance training: influence of anti-inflammatory or glucosamine treatment. Rheumatol Int. 2013 Sep;33(9):2215–24.
33.
Shah GM, Gong HS, Chae YJ, Kim YS, Kim J, Baek GH. Evaluation and management of osteoporosis and sarcopenia in patients with distal radius fractures. Clin Orthop Surg. 2020 Mar;12(1):9–21.
34.
Riuzzi F, Beccafico S, Sagheddu R, Chiappalupi S, Giambanco I, Bereshchenko O, et al. Levels of S100B protein drive the reparative process in acute muscle injury and muscular dystrophy. Sci Rep. 2017 Oct;7(1):12537.
35.
Sanajou D, Ghorbani Haghjo A, Argani H, Aslani S. AGE-RAGE axis blockade in diabetic nephropathy: current status and future directions. Eur J Pharmacol. 2018 Aug;833:158–64.
36.
Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, et al. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation. 2003 Sep;108(9):1070–7.
37.
Morozzi G, Beccafico S, Bianchi R, Riuzzi F, Bellezza I, Giambanco I, et al. Oxidative stress-induced S100B accumulation converts myoblasts into brown adipocytes via an NF-κB/YY1/miR-133 axis and NF-κB/YY1/BMP-7 axis. Cell Death Differ. 2017;24(12):2077–88.
38.
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):1204–10.
39.
Dumont NA, Wang YX, Rudnicki MA. Intrinsic and extrinsic mechanisms regulating satellite cell function. Development. 2015;142(9):1572–81.
40.
Beccafico S, Riuzzi F, Puglielli C, Mancinelli R, Fulle S, Sorci G, et al. Human muscle satellite cells show age-related differential expression of S100B protein and RAGE. Age. 2011;33(4):523–41.
41.
Lee SH, Gong HS. Measurement and interpretation of handgrip strength for research on sarcopenia and osteoporosis. J Bone Metab. 2020 May;27(2):85–96.
42.
Engelke K, Museyko O, Wang L, Laredo JD. Quantitative analysis of skeletal muscle by computed tomography imaging-State of the art. J Orthop Translat. 2018 Oct;15:91–103.
43.
Kim JS, Kim WY, Park HK, Kim MC, Jung W, Ko BS. Simple age specific cutoff value for sarcopenia evaluated by computed tomography. Ann Nutr Metab. 2017;71(3–4):157–63.
44.
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):963–75.
45.
Pillai-Kastoori L, Heaton S, Shiflett SD, Roberts AC, Solache A, Schutz-Geschwender AR. Antibody validation for Western blot: by the user, for the user. J Biol Chem. 2020;295(4):926–39.
© 2022 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2022
You do not currently have access to this content.