title: The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex.
abstract: 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.
authors.affiliation: Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Ruas
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Estall
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Rasbach
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.forename: Pontus
authors.initials: P
authors.lastname: Boström
authors.forename: Heather M
authors.initials: HM
authors.lastname: Tyra
authors.forename: Robert W
authors.initials: RW
authors.lastname: Crawford
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: D Thomas
authors.initials: DT
authors.lastname: Rutkowski
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000222:Adaptation, Physiological; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D056811:Unfolded Protein Response
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; C497250:Ddit3 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051742:Transcription Factor CHOP