Exercise improves high-fat diet-induced metabolic disorder by promoting HDAC5 degradation through the ubiquitin-proteasome system in skeletal muscle

Histone deacetylase 4/5 (HDAC4/5) are essential for regulating metabolic gene expression; AMPK alpha 2 regulates HDAC4/5 activity and the expression of MuRF1 during exercise. In this study, we used wild-type and AMPK alpha 2-/- mice to explore the potential regulatory relationship between AMPK alpha 2 and HDAC4/5 expression during exercise. Firstly, we fed C57BL/6J mice with high-fat diet for 8 weeks to assess the effects of high-fat diet on skeletal muscle metabolism and HDAC4/5 expression. We then performed a 6-week treadmill exercise on both wild-type and AMPK alpha 2-/- mice. After exercise, the expressions of HDAC4/5 were examined in both gastrocnemius and soleus. The citrate synthase activity and proteins involved in skeletal muscle oxidative process were assessed. To determine the relationship of HDAC4/5 and skeletal muscle oxidative capacity, citrate synthase activity was assessed after silencing HDAC4/5. Moreover, HDAC5 ubiquitination and the association of MuRF1 to HDAC5 were also investigated. Our results showed that 6-week exercise increased the skeletal muscle oxidative capacity and decreased HDAC4/5 expression only in soleus. HDAC5 silencing increased C2C12 cell oxidative capacity. Proteasome inhibition by MG132 abolished exercise-induced HDAC5 degradation mediated by MuRF1-ubiquitin-proteasome system. However, the ubiquitin-proteasome system (UPS) did not dominantly account for exercise-induced HDAC4 degradation. Exercise upregulated MuRF1-HDAC5 association in wild-type mice but not in AMPK alpha 2-/- mice. Our results revealed that 6-week exercise increased the skeletal muscle oxidative capacity and promoted HDAC5 degradation in soleus through the UPS, MuRF1-mediated HDAC5 ubiquitination. Although AMPK alpha 2 played a partial role in regulating MuRF1 expression and HDAC5 ubiquitination, exercise-induced HDAC5 degradation did not fully depend on AMPK alpha 2.

Automated summary

This study investigates the regulatory relationship between AMPK alpha 2 and HDAC4/5 expression during exercise. The findings suggest that exercise can enhance skeletal muscle oxidative capacity and promote HDAC5 degradation through MuRF1-mediated ubiquitination.