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Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667496/ https://www.ncbi.nlm.nih.gov/pubmed/31363081 http://dx.doi.org/10.1038/s41467-019-11265-y |
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author | Li, Mengyao Ella Lauritzen, Hans P. M. M. O’Neill, Brian T. Wang, Chih-Hao Cai, Weikang Brandao, Bruna B. Sakaguchi, Masaji Tao, Rongya Hirshman, Michael F. Softic, Samir Kahn, C. Ronald |
author_facet | Li, Mengyao Ella Lauritzen, Hans P. M. M. O’Neill, Brian T. Wang, Chih-Hao Cai, Weikang Brandao, Bruna B. Sakaguchi, Masaji Tao, Rongya Hirshman, Michael F. Softic, Samir Kahn, C. Ronald |
author_sort | Li, Mengyao Ella |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6667496 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-66674962019-08-01 Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism Li, Mengyao Ella Lauritzen, Hans P. M. M. O’Neill, Brian T. Wang, Chih-Hao Cai, Weikang Brandao, Bruna B. Sakaguchi, Masaji Tao, Rongya Hirshman, Michael F. Softic, Samir Kahn, C. Ronald Nat Commun Article 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. Nature Publishing Group UK 2019-07-30 /pmc/articles/PMC6667496/ /pubmed/31363081 http://dx.doi.org/10.1038/s41467-019-11265-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Li, Mengyao Ella Lauritzen, Hans P. M. M. O’Neill, Brian T. Wang, Chih-Hao Cai, Weikang Brandao, Bruna B. Sakaguchi, Masaji Tao, Rongya Hirshman, Michael F. Softic, Samir Kahn, C. Ronald Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism |
title | Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism |
title_full | Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism |
title_fullStr | Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism |
title_full_unstemmed | Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism |
title_short | Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism |
title_sort | role of p110a subunit of pi3-kinase in skeletal muscle mitochondrial homeostasis and metabolism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667496/ https://www.ncbi.nlm.nih.gov/pubmed/31363081 http://dx.doi.org/10.1038/s41467-019-11265-y |
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