Exercise Alleviates Sarcopenia through Activating Autophagy Mediated by miR-34a-Sirt1-FoxO3a Signaling Axis

PURPOSE: Precision mechanisms for the rehabilitation of sarcopenia upon exercise intervention remain unclear. This study aimed to investigate the role of miR-34a-mediated autophagy in the rehabilitation of sarcopenia via exercise. METHODS: Totally 10 24-month-old male mice subjected to resistance exercise were utilized to explore the role and molecular mechanisms of miR-34a-mediated autophagy in mitigating sarcopenia through RNA-Seq and miRNA screening, with identical number of same-age mice as the old control and 4-month-old mice as the youth control. The mice from exercise group were provided with ladder climbing (4*10 repetitions) on every day for 3 consecutive months. We used HE staining, RT-PCR, and Western blotting (WB) to assess muscle atrophy and to analyze signaling pathways associated with sarcopenia. Moreover, skeletal muscle-specific miR-34a and Atg7 knockout mice were used to validate the determinant role of miR-34a-mediated autophagy for sarcopenia upon exercise. RESULTS: Compared with the youth control, the aged mice exhibited obvious atrophy of skeletal muscle (p < 0.001); compared with aged mice, resistance exercise significantly delay muscular atrophy of aged mice, with suppressing the decline in the cross-sectional area (p < 0.01). Meanwhile, miRNA screening identified miR-34a as a critical miRNA, with the involvement of its hub gene Sirt1. Based on miR-34a gene knockout, the suppression of miR-34a can mimic the beneficial effects of exercise on skeletal muscle. Additionally, skeletal muscle-specific Atg7 knockout mice showed worsened muscle atrophy, highlighting the importance of autophagy. CONCLUSION: The sarcopenia delay by resistance exercise is likely through rescuing aging-induced abnormal miR-34a-mediated autophagy and suppressing miR-34a could serve as a potential alternative to exercise for individuals who cannot perform physical exercise, opening a new avenue for targeted therapies in sarcopenia rehabilitation.