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Defects in mitochondrial ATP synthesis in dystrophin-deficient Mdx skeletal muscles may be caused by Complex I insufficiency

Citation

Rybalka, E and Timpani, CA and Cooke, MB and Williams, AD and Hayes, A, Defects in mitochondrial ATP synthesis in dystrophin-deficient Mdx skeletal muscles may be caused by Complex I insufficiency, PLoS One, 9, (12) Article e115763. ISSN 1932-6203 (2014) [Refereed Article]


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Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1371/journal.pone.0115763

Abstract

Duchenne Muscular Dystrophy is a chronic, progressive and ultimately fatal skeletal muscle wasting disease characterised by sarcolemmal fragility and intracellular Ca2+ dysregulation secondary to the absence of dystrophin. Mounting literature also suggests that the dysfunction of key energy systems within the muscle may contribute to pathological muscle wasting by reducing ATP availability to Ca2+ regulation and fibre regeneration. No study to date has biochemically quantified and contrasted mitochondrial ATP production capacity by dystrophic mitochondria isolated from their pathophysiological environment such to determine whether mitochondria are indeed capable of meeting this heightened cellular ATP demand, or examined the effects of an increasing extramitochondrial Ca2+ environment. Using isolated mitochondria from the diaphragm and tibialis anterior of 12 week-old dystrophin-deficient mdx and healthy control mice (C57BL10/ScSn) we have demonstrated severely depressed Complex I-mediated mitochondrial ATP production rate in mdx mitochondria that occurs irrespective of the macronutrient-derivative substrate combination fed into the Krebís cycle, and, which is partially, but significantly, ameliorated by inhibition of Complex I with rotenone and stimulation of Complex II-mediated ATP-production with succinate. There was no difference in the MAPR response of mdx mitochondria to increasing extramitochondrial Ca2+ load in comparison to controls, and 400 nM extramitochondrial Ca2+ was generally shown to be inhibitory to MAPR in both groups. Our data suggests that DMD pathology is exacerbated by a Complex I deficiency, which may contribute in part to the severe reductions in ATP production previously observed in dystrophic skeletal muscle.

Item Details

Item Type:Refereed Article
Keywords:oxidative capacity, muscle structure
Research Division:Medical and Health Sciences
Research Group:Human Movement and Sports Science
Research Field:Exercise Physiology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cardiovascular System and Diseases
Author:Williams, AD (Associate Professor Andrew Williams)
ID Code:97655
Year Published:2014
Web of Science® Times Cited:20
Deposited By:Health Sciences A
Deposited On:2015-01-07
Last Modified:2017-10-31
Downloads:135 View Download Statistics

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