Muscle-fiber transdifferentiation in an experimental model of respiratory chain myopathy
Open accessAbstract
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.
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Damage to mitochondrial DNA results in changes in contractile properties.
“Damage to mitochondrial DNA, for instance, results in changes in contractile properties [10], highlighting the regulatory role of mitochondria in determining skeletal muscle fiber type.”
From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [10]
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- Authors
- Venhoff, N., Lebrecht, D., Pfeifer, D., Venhoff, A. C., Bissé, E., Kirschner, J., & Walker, U. A.
- Affiliations
- University Medical Center Freiburg (DE)
- University of Basel (CH)
- Corresponding author
- Venhoff, Nils
- Walker, Ulrich A
- Venue
- Arthritis Research & Therapy
- Published
- 2012-10-29
- Volume
- 14
- Issue
- 5
- Pages
- R233-R233
- ISSN
- 1478-6354 (ISSN-L)
- PMC
- PMC3580545
- OpenAlex
- W2021882159
- Cited by
- 33
- References
- 56
- Citations by year
- 2026: 2 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 1
- FWCI
- 0.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Arthritis Research & Therapy (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- mitochondrial myopathy, skeletal muscle fiber type composition, mitochondrial DNA depletion, cytochrome c oxidase deficiency, soleus muscle, neonatal myosin heavy chain, glycolytic metabolism, transcription factors, MyoD, Six1, Six2, EYA1, SOX6, estrogen-related receptor gamma, myogenin, mitochondrial function
- MeSH terms
- Animals, Disease Models, Animal, Electron Transport, Male, Mitochondria, Muscle, Muscular Atrophy, Muscular Diseases, Zidovudine, Rats, Wistar, Muscle, Skeletal, Muscle Fibers, Fast-Twitch, Muscle Fibers, Slow-Twitch, Reverse Transcriptase Inhibitors, Rats, Cell Transdifferentiation
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