Cast immobilization of hindlimb upregulates sarcolipin expression in atrophied skeletal muscles and increases thermogenesis in C57BL/6J mice.

Mechanical unloading impairs cytosolic calcium (Ca²⁺) homeostasis in skeletal muscles. In this study, we investigated whether sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) itself or one of the regulators of the Ca²⁺ SERCA pump, sarcolipin (SLN), is altered to deregulate Ca²⁺ homeostasis in cast-immobilized, atrophied muscles. Hindlimb muscles of 8-week-old male C57BL/6J mice were subjected to bilateral cast immobilization for 2 weeks. Two-week cast-immobilization induced both body weight and skeletal muscle loss. Highly phosphorylated CaMKII in the atrophied muscles suggested that cytosolic Ca²⁺ concentration was elevated. Extremely high expression levels of SLN mRNA and protein were observed in the atrophied muscles. Up-regulation of SLN at the transcriptional level was supported by low RCAN1 expression, which is a negative regulator of SLN. We treated C₂C₁₂ cells with dexamethasone to mimic muscle atrophy in vitro and showed a direct relationship between high SLN mRNA expression and low Ca²⁺ uptake by sarcoplasmic reticulum. Since SLN reportedly plays a role in non-shivering thermogenesis, we performed a cold tolerance test of the whole body. As a result, we found that mice with cast immobilization showed high cold tolerance, suggesting that cast-immobilization promoted whole-body thermogenesis. Although the activity level was decreased during cast-immobilization without change in food intake, adipose tissue weights also decreased significantly after cast immobilization. Concomitantly, we conclude that cast-immobilization of hindlimb increased thermogenesis in C57Bl/6J mice, probably via high expression of sarcolipin. [ABSTRACT FROM AUTHOR]