PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription.
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.
Sandri
Marco
M
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Lin
Jiandie
J
Handschin
Christoph
C
Yang
Wenli
W
Arany
Zoltan P
ZP
Lecker
Stewart H
SH
Goldberg
Alfred L
AL
Spiegelman
Bruce M
BM
D000818:Animals; D015415:Biomarkers; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000235:genetics*
D015415:Biomarkers; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C095278:atrophin-1