title: The unfolded protein response in relation to mitochondrial biogenesis in skeletal muscle cells.
abstract: Mitochondria comprise both nuclear and mitochondrially encoded proteins requiring precise stoichiometry for their integration into functional complexes. The augmented protein synthesis associated with mitochondrial biogenesis results in the accumulation of unfolded proteins, thus triggering cellular stress. As such, the unfolded protein responses emanating from the endoplasmic reticulum (UPRER) or the mitochondrion (UPRMT) are triggered to ensure correct protein handling. Whether this response is necessary for mitochondrial adaptations is unknown. Two models of mitochondrial biogenesis were used: muscle differentiation and chronic contractile activity (CCA) in murine muscle cells. After 4 days of differentiation, our findings depict selective activation of the UPRMTin which chaperones decreased; however, Sirt3 and UPRERmarkers were elevated. To delineate the role of ER stress in mitochondrial adaptations, the ER stress inhibitor TUDCA was administered. Surprisingly, mitochondrial markers COX-I, COX-IV, and PGC-1α protein levels were augmented up to 1.5-fold above that of vehicle-treated cells. Similar results were obtained in myotubes undergoing CCA, in which biogenesis was enhanced by ~2-3-fold, along with elevated UPRMTmarkers Sirt3 and CPN10. To verify whether the findings were attributable to the terminal UPRERbranch directed by the transcription factor CHOP, cells were transfected with CHOP siRNA. Basally, COX-I levels increased (~20%) and COX-IV decreased (~30%), suggesting that CHOP influences mitochondrial composition. This effect was fully restored by CCA. Therefore, our results suggest that mitochondrial biogenesis is independent of the terminal UPRERUnder basal conditions, CHOP is required for the maintenance of mitochondrial composition, but not for differentiation- or CCA-induced mitochondrial biogenesis.
authors.affiliation: Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
authors.forename: Zahra S
authors.initials: ZS
authors.lastname: Mesbah Moosavi
authors.affiliation: Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada dhood@yorku.ca.
authors.forename: David A
authors.initials: DA
authors.lastname: Hood
mesh_terms: D000818:Animals; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D051379:Mice; D008931:Mitochondria, Muscle / Q000502:physiology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000469:parasitology* / Q000648:ultrastructure; D001678:Organelle Biogenesis; D051742:Transcription Factor CHOP / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C497250:Ddit3 protein, mouse; D024101:Mitochondrial Proteins; D051742:Transcription Factor CHOP
keywords: CHOP; TUDCA; chronic contractile activity; mitochondria; muscle differentiation