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. Here, we show that daily heat stress treatment rescues
denervation-induced loss of mitochondria and concomitant
muscle atrophy. 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. 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 by heat stress in denervated skeletal muscle.