The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway

The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7 , encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle–specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration. Our findings link skeletal muscle contractility to metabolic homeostasis, identifying the NRF2 pathway as a key therapeutic target.