Melatonin Improves Skeletal Muscle Structure and Oxidative Phenotype by Regulating Mitochondrial Dynamics and Autophagy in Zücker Diabetic Fatty Rat Salagre Simón, Diego Raya Álvarez, Enrique Germán Cendán Martínez, Cruz Miguel Aouichat, Samira Agil Abdalla, Mhmad Ahmad Melatonin Mitochondrial fission-fusion; autophagy Oxidative stress Skeletal muscle Red vastus lateralis Muscle fiber composition Diabesity ZDF rat Obesity-induced skeletal muscle (SKM) inflexibility is closely linked to mitochondrial dysfunction. The present study aimed to evaluate the effects of melatonin on the red vastus lateralis (RVL) muscle in obese rat models at the molecular and morphological levels. Five-week-old male Zücker diabetic fatty (ZDF) rats and their age-matched lean littermates (ZL) were orally treated either with melatonin (10 mg/kg body weight (BW)/24 h) (M–ZDF and M–ZL) or non-treated (control) (C–ZDF and C–ZL) for 12 weeks. Western blot analysis showed that mitochondrial fission, fusion, and autophagy were altered in the C-ZDF group, accompanied by reduced SIRT1 levels. Furthermore, C-ZDF rats exhibited depleted ATP production and nitro-oxidative stress, as indicated by increased nitrites levels and reduced SOD activity. Western blotting of MyH isoforms demonstrated a significant decrease in both slow and fast oxidative fiber-specific markers expression in the C-ZDF group, concomitant with an increase in the fast glycolytic fiber markers. At the tissue level, marked fiber atrophy, less oxidative fibers, and excessive lipid deposition were noted in the C-ZDF group. Interestingly, melatonin treatment partially restored mitochondrial fission/fusion imbalance in the RVL muscle by enhancing the expression of fission (Fis1 and DRP1) markers and decreasing that of fusion (OPA1 and Mfn2) markers. It was also found to restore autophagy, as indicated by increased p62 protein level and LC3BII/I ratio. In addition, melatonin treatment increased SIRT1 protein level, mitochondrial ATP production, and SOD activity and decreased nitrites production. These effects were associated with enhanced oxidative phenotype, as evidenced by amplified oxidative fiber-specific markers expression, histochemical reaction for NADH enzyme, and muscular lipid content. In this study, we showed that melatonin might have potential therapeutic implications for obesity-induced SKM metabolic inflexibility among patients with obesity and T2DM 2023-10-13T12:18:00Z 2023-10-13T12:18:00Z 2023-07-27 journal article Salagre, D.; Raya Álvarez, E.; Cendan, C.M.; Aouichat, S.; Agil, A. Melatonin Improves Skeletal Muscle Structure and Oxidative Phenotype by Regulating Mitochondrial Dynamics and Autophagy in Zücker Diabetic Fatty Rat. Antioxidants 2023, 12, 1499. [https://doi.org/10.3390/antiox12081499] https://hdl.handle.net/10481/84977 10.3390/antiox12081499 eng info:eu-repo/grantAgreement/EC/ERDF/PID2021-125900OB-I00 http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional MDPI