Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism

Skeletal muscle insulin resistance, decreased phosphatidylinositol 3-kinase (P13K) activation and altered mitochondrial function are hallmarks of type 2 diabetes. To determine the relationship between these abnormalities, we created mice with muscle-specific knockout of the p110 alpha or p110 beta catalytic subunits of P13K. We find that mice with muscle-specific knockout of p110 alpha, but not p110 beta, display impaired insulin signaling and reduced muscle size due to enhanced proteasomal and autophagic activity. Despite insulin resistance and muscle atrophy, M-p11O alpha KO mice show decreased serum myostatin, increased mitochondrial mass, increased mitochondrial fusion, and increased PGC1 alpha expression, especially PCG1 alpha 2 and PCG1 alpha 3. This leads to enhanced mitochondrial oxidative capacity, increased muscle NADH content, and higher muscle free radical release measured in vivo using pMitoTimer reporter. Thus, p110 alpha is the dominant catalytic isoform of P13K in muscle in control of insulin sensitivity and muscle mass, and has a unique role in mitochondrial homeostasis in skeletal muscle.