Sesn2 is Associated with Attenuated Muscle Atrophy and Altered Expression of Key Myogenic and Autophagy Markers in Mdx Mice.

Duchenne muscular dystrophy (DMD) is a common lethal neuromuscular disorder which is characterized by progressive skeletal muscle atrophy. Despite the beneficial role of Sestrin2 (Sesn2) in improving denervation-induced skeletal muscle atrophy, the effect of Sesn2 on the skeletal muscle of DMD remains largely unknown. To regulate the expression of Sesn2, we systemically modulated its expression in mdx mice via tail-vein injection of AAV9 vectors. The tibialis anterior (TA) muscles were subsequently harvested for analysis by immunofluorescence and Western blotting to assess myofiber morphology and the protein levels of key markers of atrophy, myogenesis, and autophagy. In this study, we found that the expression levels of Sesn2 were significantly upregulated in the tibialis anterior muscle of mdx mice. Sesn2 overexpression was associated with increased myofiber cross-sectional area and reduced levels of the atrophy-related markers MuRF1 and Atrogin-1, whereas Sesn2 knockdown aggravated the expression of MuRF1 and Atrogin-1. At the molecular level, Sesn2 overexpression significantly upregulated the expression of myogenic differentiation factors (Myog and Myf5), whereas its knockdown significantly downregulated them, indicating the positive regulatory effect of Sesn2 on myogenic signaling. Additionally, the inhibition of Sesn2 significantly suppressed key autophagy markers (downregulation of pUlk1, Bec1 and LC3-II expression and accumulation of p62). Collectively, these data suggest that Sesn2 is associated with improvement in dystrophic muscle histology by coordinately influencing cellular process related to protein degradation, myogenesis and autophagy, presenting it as a potential therapeutic candidate for DMD.