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

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

SUBMITTER: Venhoff N

PROVIDER: S-EPMC3580545 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Venhoff Nils N Lebrecht Dirk D Pfeifer Dietmar D Venhoff Ana C AC Bissé Emmanuel E Kirschner Janbernd J Walker Ulrich A UA

Arthritis research & therapy 20121029 5

<h4>Introduction</h4>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.<h4>Methods</h4>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 tr ...[more]

PMID: 23107834

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Project description:Dietary fiber, with intake of soluble fibers in particular, has been reported to lower the risk for developing inflammatory bowel diseases (IBD). This is at least partly attributable to the fermentation of dietary fiber by the colonic microbiota to produce short chain fatty acids. Pectin, a widely consumed soluble fiber, is known to exert a protective effect in murine models of IBD, but the underlying mechanism remains elusive. Apart from having a prebiotic effect, it has been suggested that pectin direct influences host cells by modulating the inflammatory response in a manner dependent on its neutral sugar side chains. Here we examined the effect of the side chain content of pectin on the pathogenesis of experimental colitis in mice. Male C57BL/6 mice were fed a pectin-free diet, or a diet supplemented with characteristically high (5% orange pectin) or low (5% citrus pectin) side chain content for 10-14 days, and then administered 2,4,6-trinitrobenzene sulfonic acid or dextran sulfate sodium to induce colitis. We found that the clinical symptoms and tissue damage in the colon were ameliorated in mice that were pre-fed with orange pectin, but not in those pre-fed with citrus pectin. Although the population of CD4+Foxp+ regulatory T cells and CD4+RORγt+ inflammatory T cells in the colon were comparable between citrus and orange pectin-fed mice, colonic interleukin (IL)-1β and IL-6 levels in orange pectin-fed mice were significantly decreased. The fecal concentration of propionic acid in orange pectin-fed mice was slightly but significantly higher than that in control and citrus pectin-fed mice but the cecal concentration of propionic acid after the induction of TNBS colitis was comparable between orange and citrus pectin-fed mice. Furthermore, the protective effect of orange pectin against colitis was observed even in mice treated with antibiotics. IL-6 production from RAW264.7 cells stimulated with the toll-like receptor agonist Pam3CSK4 or lipopolysaccharide was suppressed by pre-treatment with orange pectin in vitro. Taken together, these results suggest that the side chains of pectin not only augment prebiotic effects but also directly regulate IL-6 production from intestinal host cells in a microbiota-independent fashion to attenuate colitis.

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

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

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