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DOI: 10.1101/2023.05.22.541782

Acute resistance exercise induces mitophagy and mitophagomes on subsarcolemmal clefts in human skeletal muscle: Focus on BNIP3L/NIX40 as a mitophagy flux marker

F.Diaz-Castro M. Tunon-Suarez N. Quezada ...+4 M. Castro-Sepulveda
Objective: Mitochondrial dynamics and quality control in skeletal muscle are central to healthy metabolism. Resistance exercise is a recognized tool for improving skeletal muscle function; however, its effect on mitochondria is still not fully understood. We investigated the impact of resistance exercise on mitochondrial morphology and mitophagy in human skeletal muscle. Methods: Eight healthy men performed resistance exercise on one leg, and muscle biopsies were subsequently obtained from the resting leg (Rest) and the exercised leg (Ex) to measure protein abundance and mitochondrial morphology. Additionally, muscle biopsies were obtained from twelve healthy men, and the abundance of BNIP3L protein was correlated with muscle cell and whole body health markers. Results: Ex increased p-Drp1 and decreased MFN2, Parkin, and BNIP3L protein levels. Electron microscopy indicated an increase in mitochondrial circularity, cristae abnormality, and mitophagosome structures in Ex, with a marked increase in subsarcolemmal mitophagosomes. We also identified mitophagosomes outside the muscle. Experiments in human myotubes showed a severe decrease in BNIP3L protein in response to CCCP-induced mitochondrial damage with and without bafilomycin. A positive correlation was found between BNIP3L and exercise RQ, HOMA index, while a negative correlation was found with mitophagosomes abundance and VO2max. Conclusion: Our study describes the effect of resistance exercise on mitochondrial dynamics and mitophagy in skeletal muscle, demonstrating induction of mitochondrial fission and mitophagy in the exercised leg. Moreover, we propose BNIP3L as a potential regulator and marker of mitophagy flux.