Muscle-fiber transdifferentiation in an experimental model of respiratory chain myopathy
Open Access
- 1 January 2012
- journal article
- Published by Springer Science and Business Media LLC in Arthritis Research & Therapy
- Vol. 14 (5), R233
- https://doi.org/10.1186/ar4076
Abstract
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.Keywords
This publication has 54 references indexed in Scilit:
- Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statinsToxicology and Applied Pharmacology, 2012
- FIBER TYPES IN MAMMALIAN SKELETAL MUSCLESPhysiological Reviews, 2011
- Estrogen-related Receptor γ Is a Key Regulator of Muscle Mitochondrial Activity and Oxidative CapacityJournal of Biological Chemistry, 2010
- Structural and functional changes of peripheral muscles in chronic obstructive pulmonary disease patientsCurrent Opinion in Pulmonary Medicine, 2010
- Uridine supplementation antagonizes zidovudine-induced mitochondrial myopathy and hyperlactatemia in miceArthritis & Rheumatism, 2007
- Effects of inactivity on fiber size and myonuclear number in rat soleus muscleJournal of Applied Physiology, 2005
- Exploration, normalization, and summaries of high density oligonucleotide array probe level dataBiostatistics, 2003
- Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathyHuman Molecular Genetics, 1994
- Does chronic hypoxaemia induce transformations of fibre types?Acta Physiologica Scandinavica, 1991
- Mitochondrial Myopathy Caused by Long-Term Zidovudine TherapyNew England Journal of Medicine, 1990