Lack of Musashi-2 induces type IIa fiber-dominated muscle atrophy

Skeletal muscle is a highly plastic tissue, adapting its structure and metabolism in response to diverse conditions such as contractile activity, nutrients, and diseases. Finding a novel master regulator of muscle mass and quality will provide new therapeutic targets for the prevention and treatment of muscle weakness. Musashi is an RNA-binding protein that dynamically regulates protein expression; it was originally discovered as a cell fate determination factor in neural cells. Here, we report that Musashi-2 (Msi2) is dominantly expressed in slow-type muscle fibers, fibers characterized by high metabolism and endurance. Msi2 knockout (KO) mice exhibited a decrease in both soleus myofiber size and number compared to control mice. Biochemical and histological analyses revealed that type IIa fibers, which are of the fast type but have high metabolic capacity, were decreased in Msi2 KO mice. The contraction force of isolated soleus muscle was lower in KO mice, and the expression of the metabolic proteins, cytochrome c oxidase and myoglobin, was also decreased in KO muscle. Our data demonstrate the critical role of Msi2 in the maintenance of normal fiber-type composition and metabolism.