Post - exercise whole - body heat stress additively enhances endurance training - induced 2 mitochondrial adaptations in mouse skeletal muscle

21 A recent study demonstrated that heat stress induces mitochondrial biogenesis in C2C12 22 myotubes, thereby implying that heat stress may be an effective treatment to enhance 23 endurance training-induced mitochondrial adaptations in skeletal muscle. However, 24 whether heat stress actually induces mitochondrial adaptations in skeletal muscle in vivo 25 is unclear. We herein report the novel findings that 1) whole-body heat stress produced by 26 exposure of ICR mice to a hot environment (40 oC, 30 min/day, 5 days/week, 3 weeks) 27 induced mitochondrial adaptations such as increased mitochondrial enzyme activity 28 (citrate synthase and 3-hydroxyacyl CoA dehydrogenase) and respiratory chain protein 29 content (complexes I–V) in skeletal muscle in vivo and 2) post-exercise whole-body heat 30 stress additively enhanced endurance training-induced mitochondrial adaptations 31 (treadmill running, 25 m/min, 30 min/day, 5 days/week, 3 weeks). Moreover, to 32 determine candidate mechanisms underlying mitochondrial adaptations, we investigated 33 the acute effects of post-exercise whole-body heat stress on the phosphorylation status of 34 cellular signaling cascades that subsequently induce mitochondrial gene transcription. 35 We found that whole-body heat stress boosted the endurance exercise-induced 36 phosphorylation of p38 MAPK; increased the phosphorylation status of p70S6K, a 37 biomarker of mTORC1 activity; and unexpectedly dephosphorylated AMPK and its 38 downstream target ACC in skeletal muscle. Our current observations suggest that heat 39 stress can act as an effective post-exercise treatment. Heat stress treatment appeared to be 40 clinically beneficial for people who have difficulty participating in sufficient exercise 41 training, such as the elderly, injured athletes, and patients. 42 43