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

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

Molecular and Cellular Biochemistry

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English
Article number	3412
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11265-y
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

This work was supported by NIH grants RO1DK055545 and RO1DK033201 (to C.R.K.). M.E.L. was funded by a NIH Training Grant T32 DK007260, and B.T.O. was funded by a K08 training award from the NIDDK of the NIH (K08DK100543). The Joslin Diabetes Center DRC core facility was used for part of this work (P30 DK36836).

Funders	Funder number
National Institutes of Health (NIH)	T32 DK007260, RO1DK055545, RO1DK033201
National Institute of Diabetes and Digestive and Kidney Diseases	K01DK120740, K08DK100543
National Center for Research Resources	RO1DK05554

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-11265-y

Cite this

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title = "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 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.",

author = "Li, \{Mengyao Ella\} and Lauritzen, \{Hans P.M.M.\} and O{\textquoteright}Neill, \{Brian T.\} and Wang, \{Chih Hao\} and Weikang Cai and Brandao, \{Bruna B.\} and Masaji Sakaguchi and Rongya Tao and Hirshman, \{Michael F.\} and Samir Softic and Kahn, \{C. Ronald\}",

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AU - O’Neill, Brian T.

AU - Wang, Chih Hao

AU - Cai, Weikang

AU - Brandao, Bruna B.

AU - Sakaguchi, Masaji

AU - Tao, Rongya

AU - Hirshman, Michael F.

AU - Softic, Samir

AU - Kahn, C. Ronald

PY - 2019/12/1

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N2 - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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