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Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals

Nature Medicine volume 18, pages 15751579 (2012) | Download Citation

  • A Corrigendum to this article was published on 06 December 2012

This article has been updated

Abstract

The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca2+-ATPase (Serca) pump1,2,3,4,5, is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln−/− mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca2+ leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca2+, which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism.

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Change history

  • 06 December 2012

     The authors would like to add two co-authors, A. Russell Tupling and Eric Bombardier, to the study. The author list, Acknowledgments and Author Contributions have been corrected in the HTML and PDF versions of this article.

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Acknowledgements

This work was supported in part by US National Institutes of Health grant R01 (HL080551) to M. Periasamy. N.C.B. was supported by a postdoctoral fellowship from the American Physiological Society and the American Heart Association (10POST3360007). This work was also supported in part by research grants from the Canadian Institutes of Health Research to A.R.T. (MOP 86618 and MOP 47296). We thank P. Mohler, J.A. Rafael-Fortney and J.E. Ostler, for comments on the manuscript. We thank N. Manivannan and K. Powell (Ohio State University Medical Center, Davis Heart and Lung Research Institute, Small Animal Imaging Facility, Columbus, Ohio, USA) for MRI of mice.

Author information

Author notes

    • Santosh K Maurya
    •  & Danesh H Sopariwala

    These authors contributed equally to this work.

Affiliations

  1. Department of Physiology and Cell Biology, Ohio State University, College of Medicine, Columbus, Ohio, USA.

    • Naresh C Bal
    • , Santosh K Maurya
    • , Danesh H Sopariwala
    • , Sanjaya K Sahoo
    • , Subash C Gupta
    • , Sana A Shaikh
    • , Meghna Pant
    • , Leslie A Rowland
    •  & Muthu Periasamy
  2. Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo,West Waterloo,Ontario,Canada.

    • Eric Bombardier
    •  & A Russell Tupling
  3. Howard Hughes Medical Institute, Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Sanjeewa A Goonasekera
    •  & Jeffery D Molkentin
  4. Davis Heart and Lung Research Institute, Ohio State University, Columbus, Ohio, USA.

    • Muthu Periasamy

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Contributions

M. Periasamy and N.C.B. conceived of the study idea and designed the experiments. D.H.S., S.A.S., M. Pant and L.A.R. designed and conducted mouse breeding. S.K.M., N.C.B., D.H.S. and M. Pant performed the thermogenesis experiments. N.C.B., S.C.G. and S.K.M. conducted HFD feeding experiments. S.K.S. designed and conducted chemical crosslinking studies. E.B. designed and conducted HFD experiments on Sln–/– mice. A.R.T. conceived the idea of and designed the HFD studies. S.A.G. and J.D.M. generated and characterized the Sln overexpression mouse model. M. Periasamy, S.K.M., S.K.S., N.C.B. and D.H.S. analyzed the data and assembled the figures. M. Periasamy, N.C.B. and D.H.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Muthu Periasamy.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–5

Videos

  1. 1.

    Supplementary Video 1

    Shivering is not impaired in Sln−/− mice.

  2. 2.

    Supplementary Video 2

    Curare treatment minimizes shivering.

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DOI

https://doi.org/10.1038/nm.2897

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