Document Detail

The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex.
MedLine Citation:
PMID:  21284983     Owner:  NLM     Status:  MEDLINE    
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.
Jun Wu; Jorge L Ruas; Jennifer L Estall; Kyle A Rasbach; Jang Hyun Choi; Li Ye; Pontus Boström; Heather M Tyra; Robert W Crawford; Kevin P Campbell; D Thomas Rutkowski; Randal J Kaufman; Bruce M Spiegelman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell metabolism     Volume:  13     ISSN:  1932-7420     ISO Abbreviation:  Cell Metab.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-02-02     Completed Date:  2011-05-19     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  101233170     Medline TA:  Cell Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  160-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
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MeSH Terms
Activating Transcription Factor 6 / genetics,  metabolism*
Adaptation, Physiological
Cells, Cultured
Gene Expression Regulation
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal / metabolism*
Physical Conditioning, Animal
Trans-Activators / genetics,  metabolism*
Transcription Factor CHOP / metabolism
Transcription Factors
Transcription, Genetic
Unfolded Protein Response*
Grant Support
1 U54 NS053672/NS/NINDS NIH HHS; DK54477/DK/NIDDK NIH HHS; DK61562/DK/NIDDK NIH HHS; P01 HL057346/HL/NHLBI NIH HHS; P30 DK057521/DK/NIDDK NIH HHS; R01 DK054477/DK/NIDDK NIH HHS; R01 DK054477-13/DK/NIDDK NIH HHS; R01 DK084058/DK/NIDDK NIH HHS; R01 DK084058/DK/NIDDK NIH HHS; R01 DK088227/DK/NIDDK NIH HHS; R01 DK088227-02/DK/NIDDK NIH HHS; R01 HL052173/HL/NHLBI NIH HHS; R01 HL052173/HL/NHLBI NIH HHS; R01 HL052173-14A1/HL/NHLBI NIH HHS; R03 MH089782/MH/NIMH NIH HHS; R03 MH089782-02/MH/NIMH NIH HHS; R37 DK042394/DK/NIDDK NIH HHS; R37 DK042394/DK/NIDDK NIH HHS; R37 DK042394-14/DK/NIDDK NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Activating Transcription Factor 6; 0/Atf6 protein, mouse; 0/Ddit3 protein, mouse; 0/Ppargc1a protein, mouse; 0/Trans-Activators; 0/Transcription Factors; 147336-12-7/Transcription Factor CHOP

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