Melatonin and Exercise Restore Myogenesis and Mitochondrial Dynamics Deficits Associated With Sarcopenia in iMS‐Bmal1−/− Mice Ramírez Casas, Yolanda Fernández Martínez, José Martín-Estebané, María Aranda Martínez, Paula López Rodríguez, Alba Esquivel-Ruiz, Sergio Yang, Yang Escames Rosa, Germaine Acuña Castroviejo, Darío Bmal1 Exercise melatonin Sarcopenia, a condition associated with aging, involves progressive loss of muscle mass, strength, and function, leading to impaired mobility, health, and increased mortality. The underlying mechanisms remain unclear, which limits the development of effective therapeutic interventions. Emerging evidence implicates chronodisruption as a key contributor to sarcopenia, emphasizing the role of Bmal1, a circadian clock gene critical for muscle integrity and mitochondrial function. In a skeletal muscle-specific and inducible Bmal1 knockout model (iMS-Bmal1−/−), we observed hallmark features of sarcopenia, including disrupted rhythms, impaired muscle function, and mitochondrial dysfunction. Exercise and melatonin treatment reversed these deficits independently of Bmal1. Building on these findings, the present study elucidates several mechanisms underlying these changes and the pathways by which melatonin and exercise exert their beneficial effects. Our findings indicate that iMS-Bmal1−/− mice exhibit reduced expression of satellite cell and muscle regulatory factors, indicating impaired muscle regeneration. While mitochondrial respiration remained unchanged, notable alterations in mitochondrial dynamics disrupted mitochondria in skeletal muscle. In addition, these mice showed alterations in muscle energy metabolism, compromised antioxidant defense, and inflammatory response. Remarkably, exercise and/or melatonin successfully mitigated these deficits, restoring muscle health in Bmal1-deficient mice. These findings position exercise and melatonin as promising therapeutic candidates for combating sarcopenia and emphasize the need to elucidate the molecular pathways underlying their protective effects. 2025-12-03T09:51:01Z 2025-12-03T09:51:01Z 2025-04-17 journal article Ramírez-Casas, Y., Fernández-Martínez, J., Martín-Estebané, M., Aranda-Martínez, P., López-Rodríguez, A., Esquivel-Ruiz, S., Yang, Y., Escames, G., & Acuña-Castroviejo, D. (2025). Melatonin and exercise restore myogenesis and mitochondrial dynamics deficits associated with sarcopenia in iMS-Bmal1-/- mice. Journal of Pineal Research, 77(3), e70049. https://doi.org/10.1111/jpi.70049 https://hdl.handle.net/10481/108547 10.1111/jpi.70049 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Wiley