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Caveolin-3 ( Cav3) is specifically expressed in muscle cells. Mutations in Cav3 are responsible for a group of muscle diseases called caveolinopathies, and Cav3 deficiency is associated with sarcolemmal membrane alterations, disorganization of T-tubules, and disruption of specific cell-signaling pathways. However, Cav3 overexpression increases the number of sarcolemmal caveolae and muscular dystrophy-like regenerating muscle fibers with central nuclei, suggesting that the alteration of Cav3 expression levels or localization influences muscle cell functions. Here, we used mouse C2C12 myoblasts in which Cav3 expression was suppressed with short hairpin RNA and found that Cav3 suppression impaired myotube differentiation without affecting the expression of MyoD and Myog. We also observed an increase of intracellular Ca<jats:sup>2+<\/jats:sup> levels, total calpain activity, and Ca<jats:sup>2+<\/jats:sup>-dependent calmodulin kinase II (CaMKII) levels in Cav3-depleted myoblasts. Importantly, those phenotypes due to Cav3 suppression were caused by the ryanodine receptor activation. Furthermore, pharmacological inhibition of CaMKII rescued the impairment of myoblast differentiation due to Cav3 knockdown. Our results suggest that Cav3 regulates intracellular Ca<jats:sup>2+<\/jats:sup> concentrations by modulating ryanodine receptor activity in muscle cells and that CaMKII suppression in muscle could be a novel therapy for caveolinopathies. <\/jats:p>","DOI":"10.1152\/ajpcell.00077.2022","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T11:26:12Z","timestamp":1661167572000},"page":"C1137-C1148","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Caveolin-3 regulates the activity of Ca<sup>2+<\/sup>\/calmodulin-dependent protein kinase II in C2C12 cells"],"prefix":"10.1152","volume":"323","author":[{"given":"Michio","family":"Matsunobe","sequence":"first","affiliation":[{"name":"Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan"},{"name":"Department of Biotechnology and Life Science, Tokyo University of 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