SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signaling

Abstract

Skeletal muscle atrophy occurs in several diseases and is associated with chronic stress. Studies indicate that glucocorticoid receptor signalling is the major pathway that mediates stress-induced muscle degeneration. Although the glucocorticoid signalling pathway is relatively well characterized, there is a need to identify modulators of this pathway that may be useful for drug targeting. SIRT2 is a mammalian Sirtuin known to mediate the longevity benefits of calorie restriction and exercise. Currently, the role of SIRT2 in regulating stress-induced skeletal muscle atrophy is unclear. We found that SIRT2 is a critical regulator of muscle homeostasis and is required to protect against stress-induced muscle atrophy. SIRT2 levels are reduced during glucocorticoid-induced muscle atrophy. SIRT2 deficient mice are susceptible to glucocorticoid-induced muscle atrophy, while muscle-specific SIRT2-transgenic mice exhibit improved muscle function and are protected from glucocorticoid-induced atrophy. Mechanistically, SIRT2 binds and deacetylates critical residues in the DNA-binding domain of GR and negatively affects GR activity. Our findings suggest that SIRT2 activation may protect against glucocorticoid-induced skeletal muscle atrophy.