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Open Access Research article

Muscle-fiber transdifferentiation in an experimental model of respiratory chain myopathy

Nils Venhoff1*, Dirk Lebrecht1, Dietmar Pfeifer2, Ana C Venhoff1, Emmanuel Bissé3, Janbernd Kirschner4 and Ulrich A Walker15*

Author Affiliations

1 Department of Rheumatology & Clinical Immunology, University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, 79104, Germany

2 Department of Hematology & Oncology, University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, 79104, Germany

3 Department of Clinical Chemistry, University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, 79104, Germany

4 Department of Neuropediatrics and Muscle Disorders, University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, 79104, Germany

5 Department of Rheumatology, Basel University, Burgfelderstr. 101, Basel, 4012, Switzerland

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Arthritis Research & Therapy 2012, 14:R233  doi:10.1186/ar4076

Published: 29 October 2012

Abstract

Introduction

Skeletal 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.

Methods

Ten 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.

Results

Zidovudine 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).

Conclusions

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