Parkin‐Mediated Mitophagy in Skeletal Muscle with Endurance Training

Skeletal muscle is a highly adaptive tissue that is responsive to environmental cues. With exercise training, intracellular signaling pathways are activated that promote the synthesis of mitochondria, a process termed biogenesis. The increased number of mitochondria allows for efficient substrate utilization and greater muscle endurance. However, little is known regarding mitochondrial turnover with training. Mitophagy is a process involved in the specific elimination of dysfunctional mitochondria. It is unclear if mitophagy undergoes adaptive responses in muscle with training. Parkin is a ubiquitin ligase involved in neuronal mitophagy but its role in muscle remains inconclusive. To investigate Parkin's role in muscle with exercise training, we subjected 3‐month‐old wild‐type (WT) and Parkin knock out (KO) mice to a 6‐week voluntary wheel running training paradigm. Overall, WT mice ran 28% longer than KO mice in average total running distance. Endurance training elicited 1.5‐ and 1.4‐fold increases in whole muscle mitochondrial content in WT and KO mice, respectively. Furthermore, subunits I and IV of cytochrome c oxidase and mitochondrial transcription factor A were augmented on intermyofibrillar mitochondria (IMF) isolated from hindlimb muscles of trained WT animals. This was supported by a 1.7‐fold increase in State 3 (active) IMF respiration in trained WT mice. Following 6 weeks of training, both Parkin KO and WT mice exhibited 2‐fold increases in running performance during an exhaustive bout of exercise, compared to their untrained counterparts. Interestingly, basal mitophagy flux and mitochondrial localization of LC3II were augmented by 1.5‐fold in muscle of trained WT mice. However, this increase was abolished in KO animals. Acute exercise‐induced a 2‐fold increase in LC3‐II flux in untrained WT mice, which was attenuated to a 1.6‐fold increase with training. In contrast, acute exercise decreased mitophagy flux in untrained and trained KO muscle by 10–20%. Our findings indicate that the localization of autophagy proteins to mitochondria is increased in trained muscle, but is reduced when Parkin is absent. However, during exercise‐induced mitophagy, an attenuation of autophagy proteins localized on mitochondria occurs, which is partly Parkin‐mediated. With training, exercise‐induced mitophagic signaling is reduced, likely due to enhanced mitochondrial biogenesis, leading to improved endurance. Support or Funding Information Supported by NSERC.

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