Daily heat stress treatment rescues denervation‐activated mitochondrial clearance and atrophy in skeletal muscle

Abstract

Key pointsr Traumatic nerve injury or nerve disease leads to denervation and severe muscle atrophy. Recent evidence shows that mitochondrial loss could be a key mediator of skeletal muscle atrophy.r Here, we show that daily heat stress treatment rescues denervation-induced loss of mitochondria and concomitant muscle atrophy.r We also found that denervation-activated autophagy-dependent mitochondrial clearance (mitophagy) was suppressed by daily heat stress treatment. The molecular basis of this observation is explained by our results showing that heat stress treatment attenuates the increase of key proteins that regulate the tagging step for mitochondrial clearance and the intermediate step of autophagosome formation in denervated muscle.r These findings contribute to the better understanding of mitochondrial quality control in denervated muscle from a translational perspective and provide a mechanism behind the attenuation of muscle wasting by heat stress.Abstract Traumatic nerve injury or motor neuron disease leads to denervation and severe muscle atrophy. Recent evidence indicates that loss of mitochondria and the related reduction in oxidative capacity could be key mediators of skeletal muscle atrophy. As our previous study showed that heat stress increased the numbers of mitochondria in skeletal muscle, we evaluated whether heat stress treatment could have a beneficial impact on denervation-induced loss of mitochondria and subsequent muscle atrophy. Here, we report that daily heat stress treatment (mice placed in a chamber with a hot environment; 40°C, 30 min day −1 , for 7 days) rescues the following parameters: (i) muscle atrophy (decreased gastrocnemius muscle mass); (ii) loss of mitochondrial content (decreased levels of ubiquinol-cytochrome c reductase core protein II, cytochrome c oxidase subunits I and IV and voltage-dependent anion channel protein); and (iii) reduction in oxidative capacity (reduced maximal activities of citrate synthase and 3-hydroxyacyl-CoA dehydrogenase) in denervated muscle (produced by unilateral sciatic nerve transection). In order to gain a better understanding of the above mitochondrial adaptations, we also examined the effects of heat stress on autophagy-dependent mitochondrial clearance (mitophagy). Daily heat stress normalized denervation-activated induction of mitophagy (increased mitochondrial microtubule-associated protein 1A/1B-light chain3-II (LC3-II) with and without blocker of autophagosome clearance). The molecular basis of this observation was explained by the results that heat stress attenuated the denervation-induced increase in key proteins that regulate the following steps: (i) the tagging step of mitochondrial clearance (increased mitochondrial Parkin, ubiquitin-conjugated, P62/sequestosome 1 (P62/SQSTM1)); and (ii) the elongation step of autophagosome formation (increased Atg5-Atg12 conjugate and Atg16L). Overall, our results contribute to the better understanding of mitochondrial quality control and the mechanisms behind the attenuation of muscle wasting b...

Heat stress induces mitochondrial adaptations in skeletal muscle

“…In contrast, we found that heat stress attenuates denervation-activated mitophagic flux 42) . Mitophagy is roughly divided into two processes of 1) ubiquitination of mitochondrial proteins (i.e.…”

“…Since denervation-induced mitochondrial loss can be explained by a decrease in PGC-1α, we examined the possibility that heat stress attenuates the reduction of PGC-1α by denervation. As a result, heat stress did not suppress the decrease of PGC-1α due to denervation 42) . In addition, although glucose transporter 4 (GLUT4) and fatty acid transporter/cluster of differentiation 36 (FAT/CD36), targets of PGC-1α other than mitochondria, also showed a decrease due to denervation, an improvement effect by heat stress was not observed 42) .…”

“…As a result, heat stress did not suppress the decrease of PGC-1α due to denervation 42) . In addition, although glucose transporter 4 (GLUT4) and fatty acid transporter/cluster of differentiation 36 (FAT/CD36), targets of PGC-1α other than mitochondria, also showed a decrease due to denervation, an improvement effect by heat stress was not observed 42) . These results suggest that the maintenance of the mitochondrial content by heat stress may be related to the mitochondrial-specific pathway rather than PGC-1α dependent pathway.…”

“…labeling the mitochondria to be degraded) and 2) autophagosome formation. We demonstrated that the denervation-increased proteins involved in mitochondrial ubiquitination (mitochondrial E3 Ub ligase Parkin), actual content of Ub-conjugated mitochondria and adaptor protein (mitochondrial p62) between Ub-conjugated mitochondrial proteins and autophagosome, are reduced by heat stress 42) . Regulation of autophagosome formation is classified into three steps: induction, nucleation and elongation.…”

“…Based on our previous findings, we investigated whether heat stress suppresses the decrease in mitochondria, concomitantly with skeletal muscle atrophy, in order to elucidate the mechanism by which heat stress suppresses skeletal muscle atrophy. Ten days of sciatic nerve resection (denervation; an experimental muscle disuse model) reduced skeletal muscle weight and mitochondrial content, but their reduction was suppressed by seven days of heat stress treatment during the denervation period 42) . Since denervation-induced mitochondrial loss can be explained by a decrease in PGC-1α, we examined the possibility that heat stress attenuates the reduction of PGC-1α by denervation.…”