Muscle-fiber transdifferentiation in an experimental model of respiratory chain myopathy
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
Arthritis Research & Therapy 2012, 14:R233 doi:10.1186/ar4076Published: 29 October 2012
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.
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.
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).
The type I to type II fiber transformation in mitochondrial myopathy implicates mitochondrial function as a new regulator of skeletal muscle fiber type.