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

Naresh Bal, Santosh Maurya, Danesh Sopariwala, Sanjaya Sahoo, Subash Gupta, Sana Shaikh, Meghna Pant, Leslie Rowland, Eric Bombardier, Sanjeewa Goonasekera, Russel Tupling, Jeffery Molkentin and Muthu Periasamy

Nature Medicine 2012. 18: 1575-9.


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.

Our Thoughts on This Paper

Sarcolipin Schematic

A lot of attention has been paid to mechanisms of thermogenesis, but much of this work has focused on the role of brown/beige adipose tissue. Muscle tissue is an extremely important organ for thermogenesis, as the major determinant of metabolic rate (Zurlo et al., 1990 and Nelson, et al. 1992). Understanding the mechanisms by which regulate adaptive thermogenesis is central to establishing negative energy balance to reduce obesity.

In Bal et al., 2012, the authors describe the role of sarcolipin in mediating this process. Sarcolipin is an ER localized protein, which can uncouple the SERCA ATP-dependent calcium channels (see Figure). This paper describes mice lacking the gene encoding sarcolipin (Sln) and describe how they are prone to excessive weight gain, likely due to lowered energy expenditure. By reducing the inefficient wasting of ATP due to futile cycling of calcium, these mice store more nutrients, rather than dissipating calories as heat.

In the few years since this paper was published Muthu Periasamy's group, now at Sanford-Burnham-Prebys Florida has continued this line of investigation, showing that muscle-specific overexpression of Sln has the inverse phenotype, with increased energy expenditure, and a resistance to diet-induced obesity (published in Maurya et al. 2015). This is an interesting contrast to studies on exercise performance, because they highlight the idea that inefficient muscle energy production is actually beneficial metabolically. Understanding ways by which sarcolipin and futile calcium cycling are regulated in vivo should be very important going forward.

Written by Dave Bridges on Jan. 31, 2016.


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