Constitutively active calcineurin in skeletal muscle increases endurance performance and mitochondrial respiratory capacity

Abstract

Expression of an activated form of calcineurin in skeletal muscle selectively up-regulates slow-fiber-specific gene expression. Here, we tested the hypothesis that expression of activated calcineurin in skeletal muscle influences body composition, energy homeostasis, and exercise performance. Using transgenic mice expressing activated calcineurin (CnA*) in skeletal muscle (MCK-CnA* transgenic mice), we determined whether skeletal muscle reprogramming by calcineurin activation affects exercise performance and skeletal muscle mitochondrial function. Body weight and extensor digitorum longus (EDL) skeletal muscle weight were reduced 10% in MCK-CnA* mice compared with wild-type littermates. Basal oxygen consumption, food intake, and voluntary exercise behavior were unchanged between MCK-CnA* and wild-type mice. However, when total energy expenditure was normalized by fat-free mass, energy expenditure was increased in MCK-CnA* mice. An endurance performance treadmill running test revealed MCK-CnA* mice are fatigue resistant and run 50% farther before exhaustion. After a standardized exercise bout, glycogen and triglyceride content in EDL muscle was higher in MCK-CnA* vs. wild-type mice. Mitochondrial respiratory capacity was increased 35% in EDL muscle from resting MCK-CnA* mice. In conclusion, our results provide evidence to support the hypothesis that calcineurin activation in skeletal muscle increases mitochondrial oxidative function and energy substrate storage, which contributes to enhanced endurance exercise performance. These adaptive changes occur as a consequence of a lifelong expression of a constitutively active calcineurin and mimic the response to chronic endurance training.