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Published on: March 28, 2013
PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switching,
Michael Schuler1, Faisal Ali, Céline Chambon
1IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Department of Physiological Genetics, Illkirch, F-67400 France.
Abstract:
Mice in which peroxisome proliferator-activated receptor beta (PPARbeta) is selectively ablated in skeletal muscle myocytes were generated to elucidate the role played by PPARbeta signaling in these myocytes. These somatic mutant mice exhibited a muscle fiber-type switching toward lower oxidative capacity that preceded the development of obesity and diabetes, thus demonstrating that PPARbeta is instrumental in myocytes to the maintenance of oxidative fibers and that fiber-type switching is likely to be the cause and not the consequence of these metabolic disorders. We also show that PPARbeta stimulates in myocytes the expression of PGC1alpha, a coactivator of various transcription factors, known to play an important role in slow muscle fiber formation. Moreover, as the PGC1alpha promoter contains a PPAR response element, the effect of PPARbeta on the formation and/or maintenance of slow muscle fibers can be ascribed, at least in part, to a stimulation of PGC1alpha expression at the transcriptional level.
Insights
Peroxisome proliferator-activated receptor beta (PPARbeta) is crucial for maintaining oxidative muscle fibers. Its ablation in myocytes causes fiber-type switching, leading to obesity and diabetes, not the other way around.
Area of Science:
- Muscle physiology
- Metabolic disorders
- Molecular biology
Background:
- Peroxisome proliferator-activated receptor beta (PPARbeta) is a nuclear receptor involved in various cellular processes.
- Skeletal muscle's oxidative capacity is critical for metabolic health.
- Dysregulation of muscle metabolism is linked to obesity and diabetes.
Purpose of the Study:
- To investigate the role of PPARbeta signaling specifically within skeletal muscle myocytes.
- To determine if PPARbeta influences muscle fiber type and oxidative capacity.
- To elucidate the connection between PPARbeta, muscle fiber type, and metabolic disorders.
Main Methods:
- Generation of mice with selective ablation of PPARbeta in skeletal muscle myocytes.
- Analysis of muscle fiber type composition and oxidative capacity.
- Investigation of gene expression, including PGC1alpha, in response to PPARbeta signaling.
Main Results:
- Selective PPARbeta ablation in myocytes induced a shift towards less oxidative muscle fibers.
- This fiber-type switching preceded the onset of obesity and diabetes in the mutant mice.
- PPARbeta was shown to stimulate the expression of PGC1alpha, a key factor in slow muscle fiber formation.
Conclusions:
- PPARbeta signaling in myocytes is essential for maintaining oxidative muscle fibers.
- Muscle fiber-type switching, driven by PPARbeta deficiency, is a likely cause of metabolic disorders like obesity and diabetes.
- PPARbeta's role in promoting slow muscle fiber formation is, in part, mediated by transcriptional stimulation of PGC1alpha.
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