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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Sneha Mishra & Claudia Cosentino & Ankit Kumar Tamta & Danish Khan & Shalini Srinivasan & Venkatraman Ravi & Elena Abbotto & Bangalore Prabhashankar Arathi & Shweta Kumar & Aditi Jain & Anand S. Ramai, 2022. "Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32905-w
    DOI: 10.1038/s41467-022-32905-w
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    References listed on IDEAS

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    1. Matthew F. Barber & Eriko Michishita-Kioi & Yuanxin Xi & Luisa Tasselli & Mitomu Kioi & Zarmik Moqtaderi & Ruth I. Tennen & Silvana Paredes & Nicolas L. Young & Kaifu Chen & Kevin Struhl & Benjamin A., 2012. "SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation," Nature, Nature, vol. 487(7405), pages 114-118, July.
    2. Jin Li & Mun Chun Chan & Yan Yu & Yihua Bei & Ping Chen & Qiulian Zhou & Liming Cheng & Lei Chen & Olivia Ziegler & Glenn C. Rowe & Saumya Das & Junjie Xiao, 2017. "miR-29b contributes to multiple types of muscle atrophy," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    3. Mi-Young Song & Chang Yeob Han & Young Jae Moon & Ju Hyung Lee & Eun Ju Bae & Byung-Hyun Park, 2022. "Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
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