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Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice

Insulin plays pivotal role in cellular fuel metabolism in skeletal muscle. Despite being the primary site of energy metabolism, the underlying mechanism on how insulin deficiency deranges skeletal muscle mitochondrial physiology remains to be fully understood. Here we report an important link betwee...

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Autores principales: Zabielski, Piotr, Lanza, Ian R., Gopala, Srinivas, Holtz Heppelmann, Carrie J., Bergen, H. Robert, Dasari, Surendra, Nair, K. Sreekumaran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764144/
https://www.ncbi.nlm.nih.gov/pubmed/26718503
http://dx.doi.org/10.2337/db15-0823
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author Zabielski, Piotr
Lanza, Ian R.
Gopala, Srinivas
Holtz Heppelmann, Carrie J.
Bergen, H. Robert
Dasari, Surendra
Nair, K. Sreekumaran
author_facet Zabielski, Piotr
Lanza, Ian R.
Gopala, Srinivas
Holtz Heppelmann, Carrie J.
Bergen, H. Robert
Dasari, Surendra
Nair, K. Sreekumaran
author_sort Zabielski, Piotr
collection PubMed
description Insulin plays pivotal role in cellular fuel metabolism in skeletal muscle. Despite being the primary site of energy metabolism, the underlying mechanism on how insulin deficiency deranges skeletal muscle mitochondrial physiology remains to be fully understood. Here we report an important link between altered skeletal muscle proteome homeostasis and mitochondrial physiology during insulin deficiency. Deprivation of insulin in streptozotocin-induced diabetic mice decreased mitochondrial ATP production, reduced coupling and phosphorylation efficiency, and increased oxidant emission in skeletal muscle. Proteomic survey revealed that the mitochondrial derangements during insulin deficiency were related to increased mitochondrial protein degradation and decreased protein synthesis, resulting in reduced abundance of proteins involved in mitochondrial respiration and β-oxidation. However, a paradoxical upregulation of proteins involved in cellular uptake of fatty acids triggered an accumulation of incomplete fatty acid oxidation products in skeletal muscle. These data implicate a mismatch of β-oxidation and fatty acid uptake as a mechanism leading to increased oxidative stress in diabetes. This notion was supported by elevated oxidative stress in cultured myotubes exposed to palmitate in the presence of a β-oxidation inhibitor. Together, these results indicate that insulin deficiency alters the balance of proteins involved in fatty acid transport and oxidation in skeletal muscle, leading to impaired mitochondrial function and increased oxidative stress.
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spelling pubmed-47641442017-03-01 Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice Zabielski, Piotr Lanza, Ian R. Gopala, Srinivas Holtz Heppelmann, Carrie J. Bergen, H. Robert Dasari, Surendra Nair, K. Sreekumaran Diabetes Metabolism Insulin plays pivotal role in cellular fuel metabolism in skeletal muscle. Despite being the primary site of energy metabolism, the underlying mechanism on how insulin deficiency deranges skeletal muscle mitochondrial physiology remains to be fully understood. Here we report an important link between altered skeletal muscle proteome homeostasis and mitochondrial physiology during insulin deficiency. Deprivation of insulin in streptozotocin-induced diabetic mice decreased mitochondrial ATP production, reduced coupling and phosphorylation efficiency, and increased oxidant emission in skeletal muscle. Proteomic survey revealed that the mitochondrial derangements during insulin deficiency were related to increased mitochondrial protein degradation and decreased protein synthesis, resulting in reduced abundance of proteins involved in mitochondrial respiration and β-oxidation. However, a paradoxical upregulation of proteins involved in cellular uptake of fatty acids triggered an accumulation of incomplete fatty acid oxidation products in skeletal muscle. These data implicate a mismatch of β-oxidation and fatty acid uptake as a mechanism leading to increased oxidative stress in diabetes. This notion was supported by elevated oxidative stress in cultured myotubes exposed to palmitate in the presence of a β-oxidation inhibitor. Together, these results indicate that insulin deficiency alters the balance of proteins involved in fatty acid transport and oxidation in skeletal muscle, leading to impaired mitochondrial function and increased oxidative stress. American Diabetes Association 2016-03 2015-12-30 /pmc/articles/PMC4764144/ /pubmed/26718503 http://dx.doi.org/10.2337/db15-0823 Text en © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Metabolism
Zabielski, Piotr
Lanza, Ian R.
Gopala, Srinivas
Holtz Heppelmann, Carrie J.
Bergen, H. Robert
Dasari, Surendra
Nair, K. Sreekumaran
Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice
title Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice
title_full Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice
title_fullStr Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice
title_full_unstemmed Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice
title_short Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice
title_sort altered skeletal muscle mitochondrial proteome as the basis of disruption of mitochondrial function in diabetic mice
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764144/
https://www.ncbi.nlm.nih.gov/pubmed/26718503
http://dx.doi.org/10.2337/db15-0823
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