{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:35:29Z","timestamp":1791646529642,"version":"4.3.4"},"reference-count":54,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight\/body weight (GMW\/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p &lt; 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK\/PGC-1\u03b1 signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy.<\/jats:p>","DOI":"10.3390\/metabo11050323","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T06:01:33Z","timestamp":1621317693000},"page":"323","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK\/PGC-1\u03b1 Signaling Pathway"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9958-7937","authenticated-orcid":false,"given":"Jiling","family":"Liang","sequence":"first","affiliation":[{"name":"Graduate School, Wuhan Sports University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Graduate School, Wuhan Sports University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengzhong","family":"Zeng","sequence":"additional","affiliation":[{"name":"Graduate School, Wuhan Sports University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangwen","family":"Wu","sequence":"additional","affiliation":[{"name":"Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Health Science, Wuhan Sports University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Physical Education, Hanshan Normal University, Chaozhou 521041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanju","family":"Guo","sequence":"additional","affiliation":[{"name":"Graduate School, Wuhan Sports University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Lv","sequence":"additional","affiliation":[{"name":"Graduate School, Wuhan Sports University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0906-4927","authenticated-orcid":false,"given":"Cenyi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Physical Education and Sports Science, Soochow University, Suzhou 215021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1110-5735","authenticated-orcid":false,"given":"Jingjing","family":"Fan","sequence":"additional","affiliation":[{"name":"Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Health Science, Wuhan Sports University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8191-6744","authenticated-orcid":false,"given":"Ning","family":"Chen","sequence":"additional","affiliation":[{"name":"Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Health Science, Wuhan Sports University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1016\/S0140-6736(19)31138-9","article-title":"Sarcopenia","volume":"393","author":"Sayer","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/jcsm.12147","article-title":"Welcome to the ICD-10 code for sarcopenia","volume":"7","author":"Anker","year":"2016","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/nrrheum.2017.60","article-title":"Epidemiology of sarcopenia and insight into possible therapeutic targets","volume":"13","author":"Dennison","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1113\/JP275998","article-title":"Autophagy and mitophagy flux in young and aged skeletal muscle following chronic contractile activity","volume":"596","author":"Carter","year":"2018","journal-title":"J. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"110789","DOI":"10.1016\/j.exger.2019.110789","article-title":"Regulatory role of exercise-induced autophagy for sarcopenia","volume":"130","author":"Liang","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9057593","DOI":"10.1155\/2016\/9057593","article-title":"Mitochondria in the aging muscles of flies and mice: New perspectives for old characters","volume":"2016","author":"Jaimovich","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1172\/JCI120842","article-title":"The role of mitochondria in aging","volume":"128","author":"Jang","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_8","first-page":"422","article-title":"Mitochondrial quality control and muscle mass maintenance","volume":"6","author":"Romanello","year":"2015","journal-title":"Front. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.metabol.2017.11.001","article-title":"Coordination of mitochondrial biogenesis by PGC-1\u03b1 in human skeletal muscle: A re-evaluation","volume":"79","author":"Islam","year":"2018","journal-title":"Metabolism"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"De Rezende, L.F., Rey-L\u00f3pez, J.P., Matsudo, V.K., and do Carmo Luiz, O. (2014). Sedentary behavior and health outcomes among older adults: A systematic review. BMC Public Health, 14.","DOI":"10.1186\/1471-2458-14-333"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.jshs.2019.04.002","article-title":"Exercise as a prescription for patients with various diseases","volume":"8","author":"Luan","year":"2019","journal-title":"J. Sport Health Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1002\/cphy.c110025","article-title":"Lack of exercise is a major cause of chronic diseases","volume":"2","author":"Booth","year":"2012","journal-title":"Compr. Physiol."},{"key":"ref_14","first-page":"25","article-title":"Exercise as a remedy for sarcopenia","volume":"17","author":"Landi","year":"2014","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4184","DOI":"10.1096\/fj.13-228486","article-title":"Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance","volume":"27","author":"Lira","year":"2013","journal-title":"FASEB J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.exger.2018.07.011","article-title":"Regulation of apoptosis and autophagy in mouse and human skeletal muscle with aging and lifelong exercise training","volume":"111","author":"Dethlefsen","year":"2018","journal-title":"Exp. Gerontol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Starnes, J.W., Parry, T.L., O\u2019Neal, S.K., Bain, J.R., Muehlbauer, M.J., Honcoop, A., Ilaiwy, A., Christopher, P.M., Patterson, C., and Willis, M.S. (2017). Exercise-induced alterations in skeletal muscle, heart, liver, and serum metabolome identified by non-targeted metabolomics analysis. Metabolites, 7.","DOI":"10.3390\/metabo7030040"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"C710","DOI":"10.1152\/ajpcell.00380.2014","article-title":"Role of PGC-1\u03b1 during acute exercise-induced autophagy and mitophagy in skeletal muscle","volume":"308","author":"Vainshtein","year":"2015","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.exger.2017.08.032","article-title":"The effect of exercise, resveratrol or their combination on Sarcopenia in aged rats via regulation of AMPK\/Sirt1 pathway","volume":"98","author":"Liao","year":"2017","journal-title":"Exp. Gerontol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.exger.2016.07.007","article-title":"Identification of morphological markers of sarcopenia at early stage of aging in skeletal muscle of mice","volume":"83","author":"Sayed","year":"2016","journal-title":"Exp. Gerontol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.freeradbiomed.2015.12.031","article-title":"The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass","volume":"98","author":"Rom","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yoshii, S.R., and Mizushima, N. (2017). Monitoring and measuring autophagy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091865"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0076-6879(08)03612-4","article-title":"Monitoring autophagic degradation of p62\/SQSTM1","volume":"452","author":"Lamark","year":"2009","journal-title":"Methods Enzymol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.exger.2014.04.007","article-title":"The effects of age and muscle contraction on AMPK activity and heterotrimer composition","volume":"55","author":"Hardman","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0531-5565(67)90031-9","article-title":"Ageing in irradiated and unirradiated germfree ICR mice","volume":"2","author":"Walburg","year":"1967","journal-title":"Exp. Gerontol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1093\/oxfordjournals.aje.a009520","article-title":"Epidemiology of sarcopenia among the elderly in New Mexico","volume":"147","author":"Baumgartner","year":"1998","journal-title":"Am. J. Epidemiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.coph.2017.03.009","article-title":"Skeletal muscle autophagy and its role in sarcopenia and organismal aging","volume":"34","author":"Jiao","year":"2017","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1016\/j.biocel.2013.04.023","article-title":"Protein breakdown in muscle wasting: Role of autophagy-lysosome and ubiquitin-proteasome","volume":"45","author":"Sandri","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1152\/physiol.00041.2007","article-title":"Signaling in muscle atrophy and hypertrophy","volume":"23","author":"Sandri","year":"2008","journal-title":"Physiology."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Francaux, M., Demeulder, B., Naslain, D., Fortin, R., Lutz, O., Caty, G., and Deldicque, L. (2016). Aging reduces the activation of the mTORC1 pathway after resistance exercise and protein intake in human skeletal muscle: Potential role of REDD1 and impaired anabolic sensitivity. Nutrients, 8.","DOI":"10.3390\/nu8010047"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exger.2015.02.015","article-title":"Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women","volume":"65","author":"Markofski","year":"2015","journal-title":"Exp. Gerontol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s10522-015-9598-4","article-title":"Muscle-specificity of age-related changes in markers of autophagy and sphingolipid metabolism","volume":"16","author":"Russ","year":"2015","journal-title":"Biogerontology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.freeradbiomed.2017.05.018","article-title":"Overweight in elderly people induces impaired autophagy in skeletal muscle","volume":"110","author":"Potes","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","first-page":"664","article-title":"The regulation of autophagy during exercise in skeletal muscle","volume":"120","author":"Vainshtein","year":"2016","journal-title":"J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.exger.2017.07.009","article-title":"Physical exercise increases Sestrin 2 protein levels and induces autophagy in the skeletal muscle of old mice","volume":"97","author":"Lenhare","year":"2017","journal-title":"Exp. Gerontol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s13105-013-0246-7","article-title":"Autophagic response to exercise training in skeletal muscle with age","volume":"69","author":"Kim","year":"2013","journal-title":"J. Physiol. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1089\/ars.2006.8.517","article-title":"Exercise training attenuates age-induced changes in apoptotic signaling in rat skeletal muscle","volume":"8","author":"Song","year":"2006","journal-title":"Antioxid. Redox Signal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.exger.2015.04.008","article-title":"Exercise training increases anabolic and attenuates catabolic and apoptotic processes in aged skeletal muscle of male rats","volume":"67","author":"Ziaaldini","year":"2015","journal-title":"Exp. Gerontol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7463","DOI":"10.3748\/wjg.v12.i46.7463","article-title":"Apoptosis in skeletal muscle and its relevance to atrophy","volume":"12","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1111\/acel.12399","article-title":"Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities","volume":"14","author":"Cheema","year":"2015","journal-title":"Aging Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1159\/000330064","article-title":"Apoptosis in skeletal myocytes: A potential target for interventions against sarcopenia and physical frailty\u2014A mini-review","volume":"58","author":"Marzetti","year":"2012","journal-title":"Gerontology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1039\/C7FO00127D","article-title":"Ursolic acid induces mitochondrial biogenesis through the activation of AMPK and PGC-1 in C2C12 myotubes: A possible mechanism underlying its beneficial effect on exercise endurance","volume":"8","author":"Chen","year":"2017","journal-title":"Food Funct."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.1096\/fj.14-250449","article-title":"AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity","volume":"28","author":"Lantier","year":"2014","journal-title":"FASEB J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.cmet.2018.04.014","article-title":"Maximizing cellular adaptation to endurance exercise in skeletal muscle","volume":"27","author":"Hawley","year":"2018","journal-title":"Cell Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/sj.cdd.4401784","article-title":"Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1alpha","volume":"13","author":"Bianchi","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"C217","DOI":"10.1152\/ajpcell.00070.2009","article-title":"The role of PGC-1alpha on mitochondrial function and apoptotic susceptibility in muscle","volume":"297","author":"Adhihetty","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1249\/JES.0000000000000101","article-title":"Mitochondria initiate and regulate sarcopenia","volume":"45","author":"Alway","year":"2017","journal-title":"Exerc. Sport Sci. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"E404","DOI":"10.1152\/ajpendo.00391.2017","article-title":"Parkin is required for exercise-induced mitophagy in muscle: Impact of aging","volume":"315","author":"Chen","year":"2018","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.3389\/fphys.2018.01883","article-title":"Mitochondria as a target for mitigating sarcopenia","volume":"9","author":"Coen","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.15252\/embj.201593084","article-title":"Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway","volume":"35","author":"Sorianello","year":"2016","journal-title":"EMBO J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1093\/jb\/mvr002","article-title":"Molecular mechanisms and physiologic functions of mitochondrial dynamics","volume":"149","author":"Otera","year":"2011","journal-title":"J. Biochem."},{"key":"ref_52","first-page":"1278","article-title":"Maximum oxygen consumption of rats and its changes with various experimental procedures","volume":"47","author":"Bedford","year":"1979","journal-title":"J. Appl. Physiol. Respir. Environ. Exerc. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3389\/fnagi.2020.00105","article-title":"Exercise attenuates brain aging by rescuing down-regulated Wnt\/\u03b2-Catenin signaling in aged rats","volume":"12","author":"Chen","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.biopha.2017.03.070","article-title":"Ampelopsin attenuates the atrophy of skeletal muscle from d-gal-induced aging rats through activating AMPK\/SIRT1\/PGC-1\u03b1 signaling cascade","volume":"90","author":"Kou","year":"2017","journal-title":"Biomed. Pharmacother."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/5\/323\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:03:05Z","timestamp":1760162585000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/5\/323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,18]]},"references-count":54,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["metabo11050323"],"URL":"https:\/\/doi.org\/10.3390\/metabo11050323","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,18]]}}}