The Chronology and Function of UPR Activation in Skeletal Muscle Adaptations to Chronic Contractile Activity

During exercise-induced mitochondrial biogenesis, a rapid increase in the transcription and translation of nuclear-encoded mitochondrial proteins, under the influence of PGC-1, require integration with mitochondria-derived proteins. This has the potential to perturb cellular proteostasis and thus induce an unfolded protein response from the mitochondria (UPRmt) and/or endoplasmic reticulum (UPRER). The role of the UPR in skeletal muscle, particularly with respect to exercise is not well established. We used a chronic contractile activity model over 7 days to examine the chronology of mitochondrial biogenesis, autophagy, UPRER, and UPRmt activation, and used a drug (TUDCA) to block the ER stress-induced UPR to test its role in adaptations to CCA. Our data reveal that the UPRs are involved in acute and chronic muscle adaptations, independent of CHOP signaling, to augment protein quality control. However the specific mechanism by which the UPR influences these adaptations is an important avenue of future work.