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

Abstract

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 signaling. Our results show that SIRT6 levels are increased during glucocorticoidinduced 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 glucocorticoidinduced muscle wasting. Mechanistically, we find that SIRT6 deficiency hyperactivates IGF/PI3K/AKT signaling through c-Jun transcription factormediated 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 pharmacological 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.Maintenance of skeletal muscle mass and function is crucial for the healthy life span of humans. The skeletal muscle mass is maintained by a critical balance between the protein synthesis and the degradation pathways. However, this fine balance is lost in conditions of chronic stress such as in various aging-related diseases like diabetes, cancer, renal failure, cardiac failure, AIDS, and chronic obstructive pulmonary disease 1-3 . Notably, a major contributor to chronic stress-induced muscle wasting is elevated serum levels of glucocorticoids 4,5 . In the muscle cells, glucocorticoids bind to the glucocorticoid receptor (GR), which induces its nuclear translocation and recruitment to the glucocorticoid response element (GRE). The binding of GR to GRE then alters the expression of multiple transcription factors which control the muscle atrophy program 4 . Of these, the FoxO or forkhead box transcription factors play a major role by inducing the expression of atrogenes which include specialized E3 ubiquitin ligases such as Atrogin-1/MAFbx (muscle atrophy F-box protein) and MuRF-1 (muscle RING finger-1 protein) 6,7 . Apart from increasing the rate of muscle protein degradation, glucocorticoids also inhibit protein synthesis by inhibiting the stimulatory action of insulin or IGF (Insulin-like Growth Factor) on muscle protein synthesis 8 . Although glucocorticoidinduced muscle atrophy has been extensively studied, the molecular regulator(s) capable of modulating both muscle atrophy and hypertrophy are still not we...

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Nicotinamide riboside kinases regulate skeletal muscle fiber-type specification and are rate-limiting for metabolic adaptations during regeneration

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Eldecalcitol prevents muscle loss by suppressing PI3K/AKT/FOXOs pathway in orchiectomized mice

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