The Unfolded Protein Response Mediates Adaptation to Exercise in Skeletal Muscle through a PGC-1α/ATF6α Complex
Open accessAbstract
Exercise has been shown to be effective for treating obesity and type 2 diabetes. However, the molecular mechanisms for adaptation to exercise training are not fully understood. Endoplasmic reticulum (ER) stress has been linked to metabolic dysfunction. Here we show that the unfolded protein response (UPR), an adaptive response pathway that maintains ER homeostasis upon luminal stress, is activated in skeletal muscle during exercise and adapts skeletal muscle to exercise training. The transcriptional coactivator PGC-1α, which regulates several exercise-associated aspects of skeletal muscle function, mediates the UPR in myotubes and skeletal muscle through coactivation of ATF6α. Efficient recovery from acute exercise is compromised in ATF6α(-/-) mice. Blocking ER-stress-related cell death via deletion of CHOP partially rescues the exercise intolerance phenotype in muscle-specific PGC-1α KO mice. These findings suggest that modulation of the UPR through PGC1α represents an alternative avenue to improve skeletal muscle function and achieve metabolic benefits.
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The unfolded protein response is activated in muscle by acute endurance exercise, a high-fat diet, or the combination of both stimuli.
“the unfolded protein response is activated in muscle by acute endurance exercise [42], a high-fat diet [60], or the combination of both stimuli [41].”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [42]
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References 31 · Cited by 312
- Authors
- Wu, J., Ruas, J. L., Estall, J. L., Rasbach, K. A., Choi, J. H., Ye, L., Boström, P., Tyra, H. M., Crawford, R. W., Campbell, K. P., Rutkowski, D. T., Kaufman, R. J., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- University of Iowa (US)
- University of Michigan (US)
- Corresponding author
- Spiegelman, Bruce M.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-02
- Volume
- 13
- Issue
- 2
- Pages
- 160-169
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3057411
- OpenAlex
- W2137859531
- Cited by
- 312
- References
- 31
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 26 · 2023: 17 · 2022: 21 · 2021: 19 · 2020: 23 · 2019: 20 · 2018: 28 · 2017: 27 · 2016: 12 · 2015: 16 · 2014: 12 · 2013: 32 · 2012: 19
- FWCI
- 11.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL052173, P01HL057346)
- National Institute of Mental Health (R03MH089782)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088227, DK54477, R56DK054477, R01DK084058, R37DK042394, R01DK061562, R01DK054477, DK 61562)
- National Institute of Neurological Disorders and Stroke (U54NS053672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- unfolded protein response, exercise adaptation, skeletal muscle, PGC-1α, ATF6α, endoplasmic reticulum stress, CHOP, exercise intolerance, metabolic dysfunction, type 2 diabetes, obesity, transcriptional coactivation
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adaptation, Physiological, Animals, Cells, Cultured, Gene Expression Regulation, Male, Mice, Inbred C57BL, Physical Conditioning, Animal, Transcription Factors, Transcription, Genetic, Trans-Activators, Mice, Knockout, Muscle, Skeletal, Mice, Activating Transcription Factor 6, Transcription Factor CHOP, Unfolded Protein Response
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