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. Veeranna, Tamilselvan Jayavelu, Santina Bruzzone, Raul Mostoslavsky () and Nagalingam R. Sundaresan ()
Additional contact information
Sneha Mishra: Indian Institute of Science
Claudia Cosentino: Harvard Medical School
Ankit Kumar Tamta: Indian Institute of Science
Danish Khan: Indian Institute of Science
Shalini Srinivasan: Indian Institute of Science
Venkatraman Ravi: Indian Institute of Science
Elena Abbotto: University of Genoa
Bangalore Prabhashankar Arathi: Indian Institute of Science
Shweta Kumar: Indian Institute of Science
Aditi Jain: Indian Institute of Science
Anand S. Ramaian: Anna University
Shruti M. Kizkekra: Indian Institute of Science
Raksha Rajagopal: Indian Institute of Science
Swathi Rao: Indian Institute of Science
Swati Krishna: Indian Institute of Science
Ninitha Asirvatham-Jeyaraj: Indian Institute of Technology
Elizabeth R. Haggerty: Harvard Medical School
Dafne M. Silberman: Catedra de Farmacologia, Facultad de Medicina
Irwin J. Kurland: Albert Einstein College of Medicine
Ravindra P. Veeranna: CSIR- Central Food Technological Research Institute
Tamilselvan Jayavelu: Anna University
Santina Bruzzone: University of Genoa
Raul Mostoslavsky: Harvard Medical School
Nagalingam R. Sundaresan: Indian Institute of Science

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32905-w

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