Cdk4-E2F3 signals enhance skeletal muscle oxidative function and improve whole body metabolism. Mus musculus

Skeletal muscle insulin resistance and β-cell dysfunction are signature features of type 2 diabetes (T2D) pathogenesis. We previously demonstrated a pivotal role for the cell cycle kinase, Cdk4, in regulation of β-cell mass. Here, we demonstrate that Cdk4R/R mice, which harbor constitutively active Cdk4 kinase, are resistant to obesity and diabetes. The metabolic protection is associated with Cdk4 promoting the numbers and regeneration potential of slow/oxidative muscle fibers, improved muscle mitochondrial bioenergetics and elevated E2F3 and PGC-1α expression in muscle. In contrast, muscle-specific E2F3 knockout mice exhibit poor exercise capacity and susceptibility to obesity and diabetes. Exercise induces levels of Cdk4/E2F3/PGC-1α, while those levels are suppressed in obesity. Also, levels of E2F3/PGC-1α negatively correlate with adiposity, insulin resistance and lipid accumulation in human muscle biopsies. These findings are supportive of an important role for Cdk4/E2F3 in muscle fiber type development and metabolism with therapeutic potential for metabolic and muscular diseases. Overall design: Identification of genes expressed in Control vs. Mutant (Cdk4-E2F3) mice fed with two levels of fat (RD, HFD) with three replications per group.