The Unfolded Protein Response Mediates Adaptation to Exercise in Skeletal Muscle through a PGC-1α/ATF6α Complex

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 respons...

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Published in:Cell metabolism 2011-02, Vol.13 (2), p.160-169
Main Authors: Wu, Jun, Ruas, Jorge L., Estall, Jennifer L., Rasbach, Kyle A., Choi, Jang Hyun, Ye, Li, Boström, Pontus, Tyra, Heather M., Crawford, Robert W., Campbell, Kevin P., Rutkowski, D. Thomas, Kaufman, Randal J., Spiegelman, Bruce M.
Format: Article
Language:English
Subjects:
Activating Transcription Factor 6 - genetics
Activating Transcription Factor 6 - metabolism
Adaptation, Physiological
Animals
Cells, Cultured
Gene Expression Regulation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal - metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Physical Conditioning, Animal
Trans-Activators - genetics
Trans-Activators - metabolism
Transcription Factor CHOP - metabolism
Transcription Factors
Transcription, Genetic
Unfolded Protein Response
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Summary: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. ► The UPR is activated in skeletal muscle during exercise ► PGC-1 α regulates the UPR in myotubes and skeletal muscle via coactivation of ATF6 α ► Exercise training leads to adaptation in skeletal muscle through ATF6 α-mediated UPR ► CHOP null mutation partially rescues exercise intolerance of MKO-PGC-1 α mice
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2011.01.003