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

• Marco Sandri

  *Department of Cell Biology, Harvard Medical School, Boston, MA 02115;

• Jiandie Lin

  *Department of Cell Biology, Harvard Medical School, Boston, MA 02115;

• Christoph Handschin

  *Department of Cell Biology, Harvard Medical School, Boston, MA 02115;

• Wenli Yang

  *Department of Cell Biology, Harvard Medical School, Boston, MA 02115;

• Zoltan P. Arany

  Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

• Stewart H. Lecker

  *Department of Cell Biology, Harvard Medical School, Boston, MA 02115;

• Alfred L. Goldberg

  *Department of Cell Biology, Harvard Medical School, Boston, MA 02115;

• Bruce M. Spiegelman

  *Department of Cell Biology, Harvard Medical School, Boston, MA 02115;

抄録

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.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 103 (44), 16260-16265, 2006-10-31

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1361981469348995456
• NII論文ID: 80018811036
• DOI: 10.1073/pnas.0607795103
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.0607795103
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