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

ABSTRACT: Skeletal muscle insulin resistance, decreased phosphatidylinositol 3-kinase (PI3K) 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? or p110? catalytic subunits of PI3K. We find that mice with muscle-specific knockout of p110?, but not p110?, display impaired insulin signaling and reduced muscle size due to enhanced proteasomal and autophagic activity. Despite insulin resistance and muscle atrophy, M-p110?KO mice show decreased serum myostatin, increased mitochondrial mass, increased mitochondrial fusion, and increased PGC1? expression, especially PCG1?2 and PCG1?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? is the dominant catalytic isoform of PI3K in muscle in control of insulin sensitivity and muscle mass, and has a unique role in mitochondrial homeostasis in skeletal muscle.

SUBMITTER: Li ME 

PROVIDER: S-EPMC6667496 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature