CDK4 deletion in mice prevents fat accumulation and increases endurance capacity through activation of estrogen-related receptor (ERR)-driven oxidative metabolism in skeletal muscle

Abstract

AbstractCyclin-dependent kinase 4 (CDK4) canonical role is to control cell cycle progression from G1 to S phases. However, recent studies reported that CDK4 regulates energy metabolism in non-proliferating cells such as hepatocytes or adipocytes. The objective of our work is to study CDK4 function in skeletal muscle using a model of mice lacking CDK4 (cdk4-/-). By coupling treadmill running to indirect calorimetry, we show that cdk4-/- mice display improved endurance and higher capacity to use fat as fuel during exercise. Isolated muscles lacking CDK4 are more resistant to fatigue in response to repeated contractions and have increased oxidative capacity and mitochondrial content compared to cdk4+/+ muscles. Transcriptomic analysis reveals upregulation of genes controlled by the nuclear receptors estrogen-related receptors (ERRs) in cdk4-/- skeletal muscle, associated with elevated levels of the ERR co-activator PGC1a. Supporting in vivo results, C2C12 myotubes treated with a CDK4 inhibitor have increased mitochondrial oxygen consumption, PGC1α expression and ERR transcriptional activity measured by a luciferase reporter. In normal housing conditions, cdk4-/- mice show an increased basal metabolic rate and are resistant to weight gain and fat accumulation. In conclusion, our study uncovers a role for CDK4 in the control of skeletal muscle metabolism. Moreover, CDK4 inhibition may be an alternative strategy against obesity-associated metabolic disorders.