Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling.

Chronic activation of stress hormones such as glucocorticoids leads to skeletal
muscle wasting in mammals. However, the molecular events that mediate
glucocorticoid-induced muscle wasting are not well understood. Here, we
show that SIRT6, a chromatin-associated deacetylase indirectly regulates
glucocorticoid-induced muscle wasting by modulating IGF/PI3K/AKT signal�ing. Our results show that SIRT6 levels are increased during glucocorticoid�induced reduction of myotube size and during skeletal muscle atrophy in
mice. Notably, overexpression of SIRT6 spontaneously decreases the size of
primary myotubes in a cell-autonomous manner. On the other hand, SIRT6
depletion increases the diameter of myotubes and protects them against
glucocorticoid-induced reduction in myotube size, which is associated with
enhanced protein synthesis and repression of atrogenes. In line with this, we
find that muscle-specific SIRT6 deficient mice are resistant to glucocorticoid�induced muscle wasting. Mechanistically, we find that SIRT6 deficiency
hyperactivates IGF/PI3K/AKT signaling through c-Jun transcription factor�mediated increase in IGF2 expression. The increased activation, in turn, leads
to nuclear exclusion and transcriptional repression of the FoxO transcription
factor, a key activator of muscle atrophy. Further, we find that pharmacolo�gical inhibition of SIRT6 protects against glucocorticoid-induced muscle
wasting in mice by regulating IGF/PI3K/AKT signaling implicating the role of
SIRT6 in glucocorticoid-induced muscle atrophy