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Nat Med. 2012 Oct;18(10):1575-9. doi: 10.1038/nm.2897. Epub 2012 Sep 9.

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

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

Erratum in

  • Nat Med. 2012 Dec;18(12):1857. Tupling, A Russell [added]; Bombardier, Eric [added].

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 Ca(2+)-ATPase (Serca) pump, 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 Ca(2+) 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 Ca(2+), 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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PMID:
22961106
PMCID:
PMC3676351
DOI:
10.1038/nm.2897
[PubMed - indexed for MEDLINE]
Free PMC Article
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