Sarcolipin Is a Key Determinant of the Basal Metabolic Rate, and Its Overexpression Enhances Energy Expenditure and Resistance against Diet-induced Obesity

Santosh K Maurya,Naresh C Bal,Danesh H Sopariwala,Meghna Pant,Leslie A Rowland,Sana A Shaikh,Muthu Periasamy

doi:10.1074/jbc.m115.636878

Santosh K Maurya, Naresh C Bal + Show 5 more

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https://doi.org/10.1074/jbc.m115.636878

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Abstract

Sarcolipin (SLN) is a novel regulator of sarcoplasmic reticulum Ca(2+) ATPase (SERCA) in muscle. SLN binding to SERCA uncouples Ca(2+) transport from ATP hydrolysis. By this mechanism, SLN promotes the futile cycling of SERCA, contributing to muscle heat production. We recently showed that SLN plays an important role in cold- and diet-induced thermogenesis. However, the detailed mechanism of how SLN regulates muscle metabolism remains unclear. In this study, we used both SLN knockout (Sln(-/-)) and skeletal muscle-specific SLN overexpression (Sln(OE)) mice to explore energy metabolism by pair feeding (fixed calories) and high-fat diet feeding (ad libitum). Our results show that, upon pair feeding, Sln(OE) mice lost weight compared with the WT, but Sln(-/-) mice gained weight. Interestingly, when fed with a high-fat diet, Sln(OE) mice consumed more calories but gained less weight and maintained a normal metabolic profile in comparison with WT and Sln(-/-) mice. We found that oxygen consumption and fatty acid oxidation were increased markedly in Sln(OE) mice. There was also an increase in both mitochondrial number and size in Sln(OE) muscle, together with increased expression of peroxisome proliferator-activated receptor δ (PPARδ) and PPAR γ coactivator 1 α (PGC1α), key transcriptional activators of mitochondrial biogenesis and enzymes involved in oxidative metabolism. These results, taken together, establish an important role for SLN in muscle metabolism and energy expenditure. On the basis of these data we propose that SLN is a novel target for enhancing whole-body energy expenditure.

Highlights

Sarcolipin (SLN), a regulator of SR Ca2ϩ ATPase (SERCA) in muscle, can promote the uncoupling of SERCA from Ca2ϩ transport and increase heat production
Studies have highlighted that SLN binding to SERCA uncouples ATPase activity from Ca2ϩ transport, thereby increasing ATP hydrolysis and heat production [10, 11]. By generating both loss (SlnϪ/Ϫ) and gain of function mouse models, we demonstrated recently that SLN is an important player in adaptive thermogenesis, including cold- and diet-induced thermogenesis [12]
SLN overexpression (SlnOE) mouse model in which SLN is expressed at high levels in both fast- and slow-twitch skeletal muscle tissues in comparison with WT animals [12]

Summary

Introduction

Sarcolipin (SLN), a regulator of SR Ca2ϩ ATPase (SERCA) in muscle, can promote the uncoupling of SERCA from Ca2ϩ transport and increase heat production. There was an increase in both mitochondrial number and size in SlnOE muscle, together with increased expression of peroxisome proliferator-activated receptor ␦ (PPAR␦) and PPAR ␥ coactivator 1 ␣ (PGC1␣), key transcriptional activators of mitochondrial biogenesis and enzymes involved in oxidative metabolism. These results, taken together, establish an important role for SLN in muscle metabolism and energy expenditure. On the basis of these data we propose that SLN is a novel target for enhancing whole-body energy expenditure

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