Role of P110a Subunit of PI3-kinase in Skeletal Muscle Mitochondrial Homeostasis and Metabolism

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Aug 1

PMID 31363081

Citations 14

Authors

Mengyao Ella Li

Hans P M M Lauritzen

Brian T ONeill

Chih-Hao Wang

Weikang Cai

Bruna B Brandao

Masaji Sakaguchi

Rongya Tao

Michael F Hirshman

Samir Softic

C Ronald Kahn

Affiliations

Soon will be listed here.

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 p110α or p110β catalytic subunits of PI3K. We find that mice with muscle-specific knockout of p110α, but not p110β, display impaired insulin signaling and reduced muscle size due to enhanced proteasomal and autophagic activity. Despite insulin resistance and muscle atrophy, M-p110αKO mice show decreased serum myostatin, increased mitochondrial mass, increased mitochondrial fusion, and increased PGC1α expression, especially PCG1α2 and PCG1α3. This leads to enhanced mitochondrial oxidative capacity, increased muscle NADH content, and higher muscle free radical release measured in vivo using pMitoTimer reporter. Thus, p110α 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.

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