{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:02:35Z","timestamp":1792522955171,"version":"4.5.0"},"reference-count":170,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T00:00:00Z","timestamp":1624838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP19231"],"award-info":[{"award-number":["GGP19231"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AR059646"],"award-info":[{"award-number":["AR059646"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Skeletal muscle contraction relies on both high-fidelity calcium (Ca2+) signals and robust capacity for adenosine triphosphate (ATP) generation. Ca2+ release units (CRUs) are highly organized junctions between the terminal cisternae of the sarcoplasmic reticulum (SR) and the transverse tubule (T-tubule). CRUs provide the structural framework for rapid elevations in myoplasmic Ca2+ during excitation\u2013contraction (EC) coupling, the process whereby depolarization of the T-tubule membrane triggers SR Ca2+ release through ryanodine receptor-1 (RyR1) channels. Under conditions of local or global depletion of SR Ca2+ stores, store-operated Ca2+ entry (SOCE) provides an additional source of Ca2+ that originates from the extracellular space. In addition to Ca2+, skeletal muscle also requires ATP to both produce force and to replenish SR Ca2+ stores. Mitochondria are the principal intracellular organelles responsible for ATP production via aerobic respiration. This review provides a broad overview of the literature supporting a role for impaired Ca2+ handling, dysfunctional Ca2+-dependent production of reactive oxygen\/nitrogen species (ROS\/RNS), and structural\/functional alterations in CRUs and mitochondria in the loss of muscle mass, reduction in muscle contractility, and increase in muscle damage in sarcopenia and a wide range of muscle disorders including muscular dystrophy, rhabdomyolysis, central core disease, and disuse atrophy. Understanding the impact of these processes on normal muscle function will provide important insights into potential therapeutic targets designed to prevent or reverse muscle dysfunction during aging and disease.<\/jats:p>","DOI":"10.3390\/metabo11070424","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T11:45:40Z","timestamp":1624880740000},"page":"424","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Altered Ca2+ Handling and Oxidative Stress Underlie Mitochondrial Damage and Skeletal Muscle Dysfunction in Aging and Disease"],"prefix":"10.3390","volume":"11","author":[{"given":"Antonio","family":"Michelucci","sequence":"first","affiliation":[{"name":"DNICS, Department of Neuroscience, Imaging, and Clinical Sciences, University G. d\u2019Annunzio of Chieti-Pescara, I-66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5562-350X","authenticated-orcid":false,"given":"Chen","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0213-7591","authenticated-orcid":false,"given":"Feliciano","family":"Protasi","sequence":"additional","affiliation":[{"name":"CAST, Center for Advanced Studies and Technology, DMSI, Department of Medicine and Aging Sciences, University G. d\u2019Annunzio of Chieti-Pescara, I-66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Dirksen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,28]]},"reference":[{"key":"ref_1","first-page":"2403","article-title":"Structure of sarcoplasmic reticulum","volume":"39","year":"1980","journal-title":"Fed. 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