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

Mishra, S and Cosentino, C and Tamta, AK and Khan, D and Srinivasan, S and Ravi, V and Abbotto, E and Arathi, BP and Kumar, S and Jain, A and Ramaian, AS and Kizkekra, SM and Rajagopal, R and Rao, S and Krishna, S and Asirvatham-Jeyaraj, N and Haggerty, ER and Silberman, DM and Kurland, IJ and Veeranna, RP and Jayavelu, T and Bruzzone, S and Mostoslavsky, R and Sundaresan, NR (2022) Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling. In: Nature Communications, 13 (1).

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Official URL: https://doi.org/10.1038/s41467-022-32905-w


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 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 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.

Item Type: Journal Article
Publication: Nature Communications
Publisher: Nature Research
Additional Information: The copyright for this article belongs to the Authors.
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 08 Oct 2022 03:58
Last Modified: 08 Oct 2022 03:58
URI: https://eprints.iisc.ac.in/id/eprint/77225

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