Ca 2+ leak through ryanodine receptor 1 regulates thermogenesis in resting skeletal muscle

Significance The evolution of mammals to use skeletal muscle as a source of heat allowed them to spread to all parts of the globe. The generation of heat requires increased adenosine triphosphate (ATP) hydrolysis in the resting muscle in a regulated manner, but how this mechanism works is unknown. The results suggest that mammals increase their RyR1 Ca 2+ leak rate to amplify a basal ATP turnover rate at the sarcoplasmic reticulum Ca 2+ pump that is higher than that of lower vertebrates. Muscle-based thermogenesis allows regulation of body temperature that is essential for life in mammals and provides a potential pathway for manipulating body weight or temperature by altering metabolic rate.