Diabetic cardiomyopathy refers to the changes in contractility that occur to the diabetic heart that can arise in the absence of vascular disease. Mitochondrial bioenergetic deficits and increased free radical production are pathological hallmarks of diabetic cardiomyopathy, but the mechanisms and causal relationships between mitochondrial deficits and the progression of disease are not understood. We evaluated cardiac mitochondrial function in a rodent model of chronic Type 1 diabetes (OVE26 mice) before the onset of contractility deficits. We found that the most pronounced change in OVE26 heart mitochondria is severe metabolic inflexibility. This inflexibility is characterized by large deficits in mitochondrial respiration measured in the presence of non-fatty acid substrates. Metabolic inflexibility occurred concomitantly with decreased activities of PDH (pyruvate dehydrogenase) and complex II. Hyper-acetylation of protein lysine was also observed. Treatment of control heart mitochondria with acetic anhydride (Ac2O), an acetylating agent, preferentially inhibited respiration by non-fatty acid substrates and increased superoxide production. We have concluded that metabolic inflexibility, induced by discrete enzymatic and molecular changes, including hyper-acetylation of protein lysine residues, precedes mitochondrial defects in a chronic rodent model of Type 1 diabetes.
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Research Article|
December 07 2012
Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of Type 1 diabetes
Shraddha S. Vadvalkar;
Shraddha S. Vadvalkar
*Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, U.S.A.
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C. Nathan Baily;
C. Nathan Baily
*Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, U.S.A.
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Satoshi Matsuzaki;
Satoshi Matsuzaki
*Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, U.S.A.
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Melinda West;
Melinda West
*Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, U.S.A.
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Yasvir A. Tesiram;
Yasvir A. Tesiram
†Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, U.S.A.
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Kenneth M. Humphries
Kenneth M. Humphries
1
*Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, U.S.A.
‡Department of Biochemistry and Molecular Biology, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, U.S.A.
§Reynolds Oklahoma Center on Aging, University of Oklahoma Health Science Center, 825 Northeast 13th Street, Oklahoma City, OK 73104, U.S.A.
1To whom correspondence should be addressed (email kenneth-humphries@omrf.org).
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Publisher: Portland Press Ltd
Received:
June 26 2012
Revision Received:
October 02 2012
Accepted:
October 03 2012
Accepted Manuscript online:
October 03 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 449 (1): 253–261.
Article history
Received:
June 26 2012
Revision Received:
October 02 2012
Accepted:
October 03 2012
Accepted Manuscript online:
October 03 2012
Citation
Shraddha S. Vadvalkar, C. Nathan Baily, Satoshi Matsuzaki, Melinda West, Yasvir A. Tesiram, Kenneth M. Humphries; Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of Type 1 diabetes. Biochem J 1 January 2013; 449 (1): 253–261. doi: https://doi.org/10.1042/BJ20121038
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