PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription
Proceedings of the National Academy of Sciences, 2006•National Acad Sciences
Maintaining muscle size and fiber composition requires contractile activity. Increased activity
stimulates expression of the transcriptional coactivator PGC-1α (peroxisome proliferator-
activated receptor γ coactivator 1α), which promotes fiber-type switching from glycolytic
toward more oxidative fibers. In response to disuse or denervation, but also in fasting and
many systemic diseases, muscles undergo marked atrophy through a common set of
transcriptional changes. FoxO family transcription factors play a critical role in this loss of cell …
stimulates expression of the transcriptional coactivator PGC-1α (peroxisome proliferator-
activated receptor γ coactivator 1α), which promotes fiber-type switching from glycolytic
toward more oxidative fibers. In response to disuse or denervation, but also in fasting and
many systemic diseases, muscles undergo marked atrophy through a common set of
transcriptional changes. FoxO family transcription factors play a critical role in this loss of cell …
Maintaining muscle size and fiber composition requires contractile activity. Increased activity stimulates expression of the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), which promotes fiber-type switching from glycolytic toward more oxidative fibers. In response to disuse or denervation, but also in fasting and many systemic diseases, muscles undergo marked atrophy through a common set of transcriptional changes. FoxO family transcription factors play a critical role in this loss of cell protein, and when activated, FoxO3 causes expression of the atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 and profound loss of muscle mass. To understand how exercise might retard muscle atrophy, we investigated the possible interplay between PGC-1α and the FoxO family in regulation of muscle size. Rodent muscles showed a large decrease in PGC-1α mRNA during atrophy induced by denervation as well as by cancer cachexia, diabetes, and renal failure. Furthermore, in transgenic mice overexpressing PGC-1α, denervation and fasting caused a much smaller decrease in muscle fiber diameter and a smaller induction of atrogin-1 and MuRF-1 than in control mice. Increased expression of PGC-1α also increased mRNA for several genes involved in energy metabolism whose expression decreases during atrophy. Transfection of PGC-1α into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter. Thus, the high levels of PGC-1α in dark and exercising muscles can explain their resistance to atrophy, and the rapid fall in PGC-1α during atrophy should enhance the FoxO-dependent loss of muscle mass.
National Acad Sciences