Muscle-fiber transdifferentiation in an experimental model of respiratory chain myopathyReport as inadecuate

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Arthritis Research and Therapy

, 14:R233

First Online: 29 October 2012Received: 11 May 2012Revised: 25 September 2012Accepted: 26 October 2012


IntroductionSkeletal muscle fiber composition and muscle energetics are not static and change in muscle disease. This study was performed to determine whether a mitochondrial myopathy is associated with adjustments in skeletal muscle fiber-type composition.

MethodsTen rats were treated with zidovudine, an antiretroviral nucleoside reverse transcriptase inhibitor that induces a myopathy by interfering with mitochondrial functions. Soleus muscles were examined after 21 weeks of treatment. Ten untreated rats served as controls.

ResultsZidovudine induced a myopathy with mitochondrial DNA depletion, abnormalities in mitochondrial ultrastructure, and reduced cytochrome c oxidase activity. Mitochondrial DNA was disproportionally more diminished in type I compared with type II fibers, whereas atrophy predominated in type II fibers. Compared with those of controls, zidovudine-exposed soleus muscles contained an increased proportion 256% of type II fibers, whereas neonatal myosin heavy chains remained repressed, indicating fiber-type transformation in the absence of regeneration. Microarray gene-expression analysis confirmed enhanced fast-fiber isoforms, repressed slow-fiber transcripts, and reduced neonatal fiber transcripts in the mitochondrial myopathy. Respiratory chain transcripts were diminished, whereas the enzymes of glycolysis and glycogenolysis were enhanced, indicating a metabolic adjustment from oxidative to glycolytic capacities. A coordinated regulation was found of transcription factors known to orchestrate type II fiber formation upregulation of MyoD, Six1, Six2, Eya1, and Sox6, and downregulation of myogenin and ERRγ.

ConclusionsThe type I to type II fiber transformation in mitochondrial myopathy implicates mitochondrial function as a new regulator of skeletal muscle fiber type.

AbbreviationsCOPDchronic obstructive pulmonary disease

COXcytochrome c oxidase

ERRestrogen-related receptor

IQRinterquartile ranges

MHCmyosin heavy chain

MRFmyogenic regulatory factor

mtDNAmitochondrial DNA

NADH-DHnicotinamide adenine dinucleotide hydrogen dehydrogenase

nDNAnuclear DNA

SDstandard deviation

SDHsuccinate dehydrogenase.

Electronic supplementary materialThe online version of this article doi:10.1186-ar4076 contains supplementary material, which is available to authorized users.

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Author: Nils Venhoff - Dirk Lebrecht - Dietmar Pfeifer - Ana C Venhoff - Emmanuel Bissé - Janbernd Kirschner - Ulrich A Walker


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