Sarcolipin Is a Newly Identified Regulator of Muscle-Based Thermogenesis in Mammals

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Animals
  • Body Temperature Regulation / physiology*
  • Calcium / metabolism
  • Cell Line
  • Energy Metabolism / genetics
  • HEK293 Cells
  • Humans
  • Ion Channels / deficiency
  • Ion Channels / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / genetics
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / metabolism
  • Obesity / genetics
  • Proteolipids / deficiency
  • Proteolipids / genetics
  • Proteolipids / metabolism*
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sarcoplasmic Reticulum / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • Thermogenesis / physiology*
  • Uncoupling Protein 1

Substances

  • Ion Channels
  • Mitochondrial Proteins
  • Muscle Proteins
  • Proteolipids
  • Ryanodine Receptor Calcium Release Channel
  • UCP1 protein, human
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • sarcolipin
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium