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

Sneha Mishra, Claudia Cosentino, Ankit Kumar Tamta, Danish Khan, Shalini Srinivasan, Venkatraman Ravi, Elena Abbotto, Bangalore Prabhashankar Arathi, Shweta Kumar, Aditi Jain, Anand S. Ramaian, Shruti M. Kizkekra, Raksha Rajagopal, Swathi Rao, Swati Krishna, Ninitha Asirvatham-Jeyaraj, Elizabeth R. Haggerty, Dafne M. Silberman, Irwin J. Kurland, Ravindra P. VeerannaTamilselvan Jayavelu, Santina Bruzzone, Raul Mostoslavsky, Nagalingam R. Sundaresan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 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.

Original languageEnglish (US)
Article number5415
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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