title: Muscle-fiber transdifferentiation in an experimental model of respiratory chain myopathy.
abstract: BACKGROUND
  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.
authors.forename: Nils
authors.initials: N
authors.lastname: Venhoff
authors.forename: Dirk
authors.initials: D
authors.lastname: Lebrecht
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Ana C
authors.initials: AC
authors.lastname: Venhoff
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bissé
authors.forename: Janbernd
authors.initials: J
authors.lastname: Kirschner
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Walker
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D004195:Disease Models, Animal; D004579:Electron Transport / Q000502:physiology*; D008297:Male; D008931:Mitochondria, Muscle / Q000502:physiology / Q000648:ultrastructure; D018656:Muscle Fibers, Fast-Twitch / Q000473:pathology*; D018657:Muscle Fibers, Slow-Twitch / Q000473:pathology*; D018482:Muscle, Skeletal / Q000473:pathology; D009133:Muscular Atrophy / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects; D015215:Zidovudine / Q000009:adverse effects
chemical_list: D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine