Parkin Overexpression Attenuates Aging‐related Muscle Atrophy in Mice

One of the most significant changes associated with normal aging is a progressive loss of muscle mass and strength, a biological process termed sarcopenia. Solid experimental evidence indicates that mitochondrial dysfunctions (i) accumulate with muscle aging and (ii) are causally involved in sarcopenia. Recent findings suggest that mitophagy, the process in charge of the removal of damaged/dysfunctional mitochondria, is altered in aged muscle. Impaired mitophagy represents an attractive mechanism that could contribute to the accumulation of mitochondrial dysfunctions and sarcopenia. To test this hypothesis, we investigated the impact of Parkin overexpression in skeletal muscles of young and old mice. Parkin was overexpressed for 4 months in the tibialis anterior and gastrocnemius muscles of young (3 months old at the time of injection; 7 months old at the time of sacrifice) and late middle‐aged (18 months old at the time of injection; 22 months old at the time of sacrifice) mice using intramuscular injections of Adeno‐Associated Viruses (AAV). The expression of Parkin was driven in our viral construction by the muscle specific promoter MCK (Muscle Creatine Kinase). A control AAV, containing a sequence coding for the green fluorescent protein, was injected in the contralateral leg. As hypothesized, old control (GFP expressing) muscles displayed lower muscle weights and fiber cross‐sectional area as compared to their young adult counterparts. In both young and old animals Parkin‐overexpressing muscles displayed higher weights, fiber cross‐sectional area and complex II activity. In old mice, Parkin‐overexpressing muscles exhibited higher expression of complex II, complex IV and PGC‐1α. In line with these results, Parkin overexpressing muscles in aged animals exhibited a higher mitochondrial density on transmission electron micrographs. Old GFP expressing muscles displayed a higher 4‐hydroxynonenal content, a marker of oxidative stress, as compared to their young adult counterparts. Remarkably, Parkin overexpressing muscles in old mice had lower 4‐hydroxynonenal content vs their GFP counterparts. GFP expressing muscles of old mice also showed a higher type I collagen content as compared to their young adult counterparts, a sign of aging‐related fibrosis. Interestingly, Parkin overexpression in old mice was associated with lower type I collagen content. In conclusion, our results indicate that Parkin overexpression in old muscles attenuated sarcopenia, increased mitochondrial biogenesis and density, decreased oxidative stress and attenuated fibrosis. In young muscles, Parkin overexpression unexpectedly caused hypertrophy. Our results therefore suggest that Parkin might be an effective therapeutic target to counteract sarcopenia and to positively influence muscle function in young adults. Further studies are now required to dissect the mechanisms underlying the positive impacts of Parkin overexpression in young and aging skeletal muscles. Support or Funding Information This work was supported by the National sciences and Engineering Research Council of Canada and the Quebec Research Network on Aging

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