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Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16260-5. Epub 2006 Oct 19.

PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription.

Author information

1
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.

Abstract

Maintaining muscle size and fiber composition requires contractile activity. Increased activity stimulates expression of the transcriptional coactivator PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1alpha), 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-1alpha and the FoxO family in regulation of muscle size. Rodent muscles showed a large decrease in PGC-1alpha mRNA during atrophy induced by denervation as well as by cancer cachexia, diabetes, and renal failure. Furthermore, in transgenic mice overexpressing PGC-1alpha, 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-1alpha also increased mRNA for several genes involved in energy metabolism whose expression decreases during atrophy. Transfection of PGC-1alpha 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-1alpha in dark and exercising muscles can explain their resistance to atrophy, and the rapid fall in PGC-1alpha during atrophy should enhance the FoxO-dependent loss of muscle mass.

PMID:
17053067
PMCID:
PMC1637570
DOI:
10.1073/pnas.0607795103
[Indexed for MEDLINE]
Free PMC Article

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