The sarcoplasmic reticulum and SERCA: a nexus for muscular adaptive thermogenesis

We are currently facing an "obesity epidemic" worldwide. Promoting inefficient metabolism in muscle represents a potential treatment for obesity and its complications. Sarco(endo)plasmic reticulum (SR) Ca²⁺-ATPase (SERCA) pumps in muscle are responsible for maintaining low cytosolic Ca²⁺ concentration through the ATP-dependent pumping of Ca²⁺ from the cytosol into the SR lumen. SERCA activity has the potential to be a critical regulator of body mass and adiposity given that it is estimated to contribute upwards of 20% of daily energy expenditure. More interestingly, this fraction can be modified physiologically in the face of stressors, such as ambient temperature and diet, through its physical interaction with several regulators known to inhibit Ca²⁺ uptake and muscle function. In this review, we discuss advances in our understanding of Ca²⁺-cycling thermogenesis within skeletal muscle, focusing on SERCA and its protein regulators, which were thought previously to only modulate muscular contractility. Novelty ATP consumption by SERCA pumps comprises a large proportion of resting energy expenditure in muscle and is dynamically regulated through interactions with small SERCA regulatory proteins. SERCA efficiency correlates significantly with resting metabolism, such that individuals with a higher resting metabolic rate have less energetically efficient SERCA Ca²⁺ pumping in muscle (i.e., lower coupling ratio). Futile Ca²⁺ cycling is a versatile heat generating mechanism utilized by both skeletal muscle and beige fat.