Affiliation:
1. School of Kinesiology and Health Science, York University, Toronto, ON, Canada
2. Muscle Health Research Centre, York University, Toronto, ON, Canada
Abstract
The maintenance of muscle health with advancing age is dependent on mitochondrial homeostasis. While reductions in mitochondrial biogenesis have been observed with age, less is known regarding organelle degradation. Parkin is an E3 ubiquitin ligase implicated in mitophagy, but few studies have examined Parkin’s contribution to mitochondrial turnover in muscle. Wild-type (WT) and Parkin knockout (KO) mice were used to delineate a role for Parkin-mediated mitochondrial degradation in aged muscle, in concurrence with exercise. Aged animals exhibited declines in muscle mass and mitochondrial content, paralleled by a nuclear environment endorsing the transcriptional repression of mitochondrial biogenesis. Mitophagic signaling was enhanced following acute endurance exercise in young WT mice but was abolished in the absence of Parkin. Basal mitophagy flux of the autophagosomal protein lipidated microtubule-associated protein 1A/1B-light chain 3 was augmented in aged animals but did not increase additionally with exercise when compared with young animals. In the absence of Parkin, exercise increased the nuclear localization of Parkin-interacting substrate, corresponding to a decrease in nuclear peroxisome proliferator gamma coactivator-1α. Remarkably, exercise enhanced mitochondrial ubiquitination in both young WT and KO animals. This suggested compensation of alternative ubiquitin ligases that were, however, unable to restore the diminished exercise-induced mitophagy in KO mice. Under basal conditions, we demonstrated that Parkin was required for mitochondrial mitofusin-2 ubiquitination. We also observed an abrogation of exercise-induced mitophagy in aged muscle. Our results demonstrate that acute exercise-induced mitophagy is dependent on Parkin and attenuated with age, which likely contributes to changes in mitochondrial content and quality in aging muscle.
Funder
Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)
Canada Research Chairs (Chaires de recherche du Canada)
Publisher
American Physiological Society
Subject
Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism
Cited by
68 articles.
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