Mitochondrial Quality Control Regulation by p53 During Disuse‐Induced Atrophy

Abstract

Chronic muscle disuse, as observed in conditions of aging, prolonged bedrest, or limb immobilization, contributes to progressive atrophy of the affected skeletal muscle, and a reduction in mitochondrial content. These alterations in muscle mass and aerobic potential have broader consequences on mobility, strength and overall metabolic health. At the molecular level, chronic disuse results in increased intracellular reactive oxygen species (ROS) levels and elevated protein degradation. p53 is a well‐known transcriptional regulator that responds rapidly to perturbations in the cellular environment to activate various pathways in order to reestablish homeostasis. Previous work has illustrated a role for p53 in skeletal muscle mitochondrial maintenance as well as a contribution to muscle atrophy following chronic disuse. Our investigation focused on the necessity of p53 in mediating mitochondrial quality control (MQC) and muscle atrophy following 3 and 7 days of denervation‐induced muscle disuse in both wildtype (WT) and p53 muscle‐specific knockout (mKO) mice. Tibialis anterior (TA) mass was significantly reduced by 16% following 7 days of denervation in WT animals, however this was attenuated to only a 7% reduction in the mKO mice. Genotype had no effect on changes in mitochondrial content as both WT and mKO animals exhibited similar reductions (10–13%) in COX Activity by 7 days of denervation. Despite similar changes in mitochondrial content, there were divergent responses in mitochondrial function, assessed via O‐2 consumption and ROS emission using high‐resolution respirometry. Denervation resulted in impaired respiration in both genetic backgrounds, however we observed a trend for further decrements in the mKO mice as well as concomitant blunting of ROS generation following 7 days. To examine the regulation of MQC, we measured nuclear and mitochondrial localization of the transcriptional regulator PGC‐1α, as well as markers of autophagy/mitophagy, lysosomal biogenesis, the mitochondrial unfolded protein response (UPRmt) and apoptosis. We observed no effect of 3 days of denervation in any of the MQC markers. Following 7 days, nuclear PGC‐1α protein expression was elevated nearly 2‐fold in the denervated muscle of mKO mice, whereas WT animals displayed no change. Conversely, mitochondrial PGC‐1α protein expression was reduced almost 50% in WT denervated muscle but was maintained in the mKO tissue. Moreover, chronic disuse resulted in 3–6‐fold increases in the autophagy/mitophagy proteins p62, LC3‐II, PINK1 and Parkin in isolated mitochondrial fractions from WT mice, but mKO animals showed a diminished induction of these markers. In contrast, lysosomal proteins Lamp1 and Cathepsin D were induced by 40–50% in mKO muscle compared to WT animals. Similarly, UPRmt proteins mtHSP70, LonP, and ATF5 were elevated 15–30% higher in the denervated muscle of mKO animals, while the apoptotic marker BAX and BID were attenuated relative to WT counterparts. Together, these results suggest a dysregulation of MQC in the absence of p53 within skeletal muscle subjected to denervation, and indicate a potential role of p53 in contributing to organelle maintenance during muscle atrophy.Support or Funding InformationWork supported by NSERC, Canada.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.