Sarcolipin is a novel regulator of muscle based thermogenesis and metabolism in mammals

Abstract

Sarcolipin (SLN) is a novel regulator of Sarco/Endoplasmic Reticulum Ca2+‐ATPase (SERCA) pump and it is expressed exclusively in striated muscle. Recent in‐vitro studies suggested that SLN can increase heat production by uncoupling SERCA‐mediated ATP hydrolysis from Ca2+ transport but its role in muscle physiology has not been established. To demonstrate that SLN is the basis for muscle thermogenesis in vivo, we challenged SLN−/− mice to acute cold (4°C). Here we show that SLN−/− mice without interscapular Brown Adipose Tissue (iBAT) failed to maintain core body temperature (Tc, 37°C) and died when exposed to acute cold (4°C), whereas wildtype (WT) mice without iBAT were able to maintain Tc. Overexpression of SLN in the null background fully restored muscle‐based thermogenesis, suggesting that SLN is the basis for SERCA‐mediated heat production. We found that curare mediated blockade of shivering in WT mice without iBAT did not significantly compromise thermogenesis indicating existence of non‐shivering thermogenesis (NST) in muscle. We show that Ryanodine receptor (RyR1)‐mediated Ca2+ leak is an important mechanism for SERCA‐activated heat generation. We also provide experimental data to suggest that SLN can interact with SERCA in the presence of Ca2+ and is thereby capable of promoting uncoupling of the SERCA pump and increasing heat production. We further demonstrate 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 this mechanism could be recruited in energy metabolism.