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

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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Figure 1: Sln−/− mice are not able to maintain optimal core temperature (37 °C) and develop hypothermia when challenged with acute cold.
Figure 2: Reintroduction of Sln in Sln−/− mice completely restores thermogenesis, and Sln is necessary for muscle-based NST.
Figure 3: Molecular basis of Sln-mediated thermogenesis.
Figure 4: Sln−/− mice are prone to develop obesity when fed HFD.

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.

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Authors and Affiliations

Authors

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.

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Correspondence to Muthu Periasamy.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 575 kb)

Supplementary Video 1

Shivering is not impaired in Sln−/− mice. (MP4 12606 kb)

Supplementary Video 2

Curare treatment minimizes shivering. (MP4 13584 kb)

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Bal, N., Maurya, S., Sopariwala, D. et al. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat Med 18, 1575–1579 (2012). https://doi.org/10.1038/nm.2897

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