Cited by 974Muscle Physiology and DisordersAdipose Tissue and MetabolismMetabolism, Diabetes, and Cancer

The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.

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

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Abstract

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.

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Research works printed but not linked: 7

  1. JM Sacheck, J-P Hyatt, A Raffaello, RT Jagoe, RR Roy, VR Edgerton, SH Lecker, AL Goldberg FASEB J, in press. (2006).
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Metadata

Authors
Sandri, M., Lin, J., Handschin, C., Yang, W., Arany, Z. P., Lecker, S. H., Goldberg, A. L., & Spiegelman, B. M.
Affiliations
  • Harvard University (US)
  • Beth Israel Deaconess Medical Center (US)
Venue
Proceedings of the National Academy of Sciences
Published
2006-10-31
Volume
103
Issue
44
Pages
16260-16265
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W1977548231
Cited by
974
References
53
Citations by year
2026: 20 · 2025: 38 · 2024: 44 · 2023: 51 · 2022: 56 · 2021: 42 · 2020: 66 · 2019: 64 · 2018: 54 · 2017: 40 · 2016: 51 · 2015: 57 · 2014: 65 · 2013: 68 · 2012: 52
FWCI
13.20
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • edoc (University of Basel) (submittedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • edoc (University of Basel)
Funders
  • Muscular Dystrophy Association
  • Compagnia di San Paolo
  • National Institutes of Health (DK6230701)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-6230701, R01DK062307, R56DK054477, P30DK040561)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
PGC-1α, skeletal muscle atrophy, FOXO3, atrogin-1, MuRF1, ubiquitin ligase, denervation, cancer cachexia, diabetes mellitus, renal failure, fasting, physical activity, muscle fiber diameter, energy metabolism, transcriptional coactivator, muscle fiber type shift
MeSH terms
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Gene Expression Regulation, Mice, Transgenic, Muscular Atrophy, Nerve Tissue Proteins, Transcription Factors, Transcription, Genetic, Biomarkers, Trans-Activators, Muscle, Skeletal, Mice, Forkhead Transcription Factors

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