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

Mengyao Ella Li; Hans P M M Lauritzen; Brian T O'Neill; Chih-Hao Wang; Weikang Cai; Bruna B Brandao; Masaji Sakaguchi; Rongya Tao; Michael F Hirshman; Samir Softic; C Ronald Kahn

doi:10.1038/s41467-019-11265-y

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

Journal article

Open access

Peer reviewed

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

Mengyao Ella Li, Hans P M M Lauritzen, Brian T O'Neill, Chih-Hao Wang, Weikang Cai, Bruna B Brandao, Masaji Sakaguchi, Rongya Tao, Michael F Hirshman, Samir Softic, …

Nature communications, Vol.10(1), pp.3412-14

07/30/2019

DOI: 10.1038/s41467-019-11265-y

PMCID: PMC6667496

PMID: 31363081

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https://doi.org/10.1038/s41467-019-11265-yView

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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.

Animals

Class I Phosphatidylinositol 3-Kinases - genetics

Class I Phosphatidylinositol 3-Kinases - metabolism

Homeostasis

Insulin - metabolism

Male

Mice

Mice, Inbred C57BL

Mice, Knockout

Mitochondria - enzymology

Mitochondria - genetics

Mitochondria - metabolism

Muscle, Skeletal - enzymology

Muscle, Skeletal - metabolism

NAD - metabolism

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism

Phosphatidylinositol 3-Kinases - genetics

Phosphatidylinositol 3-Kinases - metabolism

Details

Title: Subtitle: Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism
Creators: Mengyao Ella Li - Joslin Diabetes Center
Hans P M M Lauritzen - Joslin Diabetes Center
Brian T O'Neill - University of Iowa
Chih-Hao Wang - Joslin Diabetes Center
Weikang Cai - Joslin Diabetes Center
Bruna B Brandao - Joslin Diabetes Center
Masaji Sakaguchi - Joslin Diabetes Center
Rongya Tao - Boston Children's Hospital
Michael F Hirshman - Joslin Diabetes Center
Samir Softic - Boston Children's Hospital
C Ronald Kahn - Joslin Diabetes Center
Resource Type: Journal article
Publication Details: Nature communications, Vol.10(1), pp.3412-14
DOI: 10.1038/s41467-019-11265-y
PMID: 31363081
PMCID: PMC6667496
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: T32 DK007260 / NIDDK NIH HHS K01 DK120740 / NIDDK NIH HHS P30 DK036836 / NIDDK NIH HHS R01 DK033201 / NIDDK NIH HHS R01 DK055545 / NIDDK NIH HHS K08 DK100543 / NIDDK NIH HHS
Language: English
Date published: 07/30/2019
Academic Unit: Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984359815802771

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