Skeletal Muscle Thermogenesis and Its Role in Whole Body Energy Metabolism

Abstract

Obesity and diabetes has become a major epidemic across the globe. Controlling obesity has been a challenge since this would require either increased physical activity or reduced caloric intake; both are difficult to enforce. There has been renewed interest in exploiting pathways such as uncoupling protein 1 (UCP1)-mediated uncoupling in brown adipose tissue (BAT) and white adipose tissue to increase energy expenditure to control weight gain. However, relying on UCP1-based thermogenesis alone may not be sufficient to control obesity in humans. On the other hand, skeletal muscle is the largest organ and a major contributor to basal metabolic rate and increasing energy expenditure in muscle through nonshivering thermogenic mechanisms, which can substantially affect whole body metabolism and weight gain. In this review we will describe the role of Sarcolipin-mediated uncoupling of Sarcoplasmic Reticulum Calcium ATPase (SERCA) as a potential mechanism for increased energy expenditure both during cold and diet-induced thermogenesis.

Keywords: ATP hydrolysis; Calcium cycling; Diabetes mellitus; Obesity; Sarcolipin; Sarcoplasmic reticulum calcium-transporting ATPases; Skeletal muscle thermogenesis.

Fig. 1. Proposed mechanism to show how sarcolipin (SLN)/sarcoendoplasmic reticulum calcium APTase (SERCA) interaction affects muscle metabolism. SERCA uses adenosine triphosphate (ATP) hydrolysis to actively transport Ca²⁺ from the cytosol into the sarcoplasmic reticulum lumen. SLN and Ca²⁺ bind competitively to SERCA during Ca²⁺ transport. SLN binding to SERCA does not inhibit ATP hydrolysis but prevents Ca²⁺ transport by a mechanism named uncoupling, where Ca²⁺ slips back into cytosol. Uncoupling of SERCA leads to futile cycling of the SERCA pump resulting in increased ATP hydrolysis/heat production; thus, creating energy demand. Uncoupling of SERCA increases cytosolic Ca²⁺ acutely, thereby promoting Ca²⁺ entry into mitochondria matrix activating the oxidative metabolism and ATP synthesis. RyR1, ryanodine receptor 1; ADP, adenosine diphosphate; Pi, inorganic phosphate.