Journal
CELL METABOLISM
Volume 13, Issue 2, Pages 160-169Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2011.01.003
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Funding
- National Institutes of Health (NIH) [DK61562, DK54477, 1137, DK042394, R01 HL052173, P01 HL057346]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK084058]
- Wellstone Muscular Dystrophy Cooperative Research Center [U54 NS053672]
- Howard Hughes Medical Institute
- American Heart Association [POST2010078]
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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-1 alpha, which regulates several exercise-associated aspects of skeletal muscle function, mediates the UPR in myotubes and skeletal muscle through coactivation of ATF6 alpha. Efficient recovery from acute exercise is compromised in ATF6 alpha(-/-) mice. Blocking ER-stress-related cell death via deletion of CHOP partially rescues the exercise intolerance phenotype in muscle-specific PGC-1 alpha KO mice. These findings suggest that modulation of the UPR through PGC1 alpha represents an alternative avenue to improve skeletal muscle function and achieve metabolic benefits.
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