ATF5 is required for the normal stress response during skeletal muscle denervation

ABSTRACT Denervation induces muscle atrophy, as well as a decrease in mitochondrial content and function. The cellular defence in response to this includes the Integrated Stress Response (ISR) and the Mitochondrial Unfolded Protein Response (UPR mt ). These pathways restore homeostasis by reducing global protein synthesis while activating transcription factors such as ATF5 to induce changes in gene expression. Our objective was to characterize the regulatory role of ATF5 on the ISR/UPR mt during mitochondrial stress brought about by muscle denervation. Denervation resulted in a decrease in the mass of all muscle groups. This was accompanied by increases in p62, LC3I/II, and Beclin1 proteins, indicative of elevated autophagy in both WT and KO animals. ISR activation was confirmed by increases in ATF4, CHOP and eIF2α proteins in WT animals, but this was blunted in the absence of ATF5. Likewise, the induction of proteins of the UPR mt was impaired in ATF5 KO mice following denervation. Antioxidant proteins NQO1 and HO1 were lower in ATF5 KO mice compared to WT controls. However, mitochondrial content, estimated using COX activity and SDH staining, was better maintained during denervation in the absence of ATF5, suggesting that ATF5 normally contributes to their decline. Although some differences were noted in the responses to denervation between male and female mice, most changes were similar between sexes. Thus, denervation resulted in robust elevations in ISR, UPR mt , autophagy, lysosomal and antioxidant-related proteins in WT mice, and the ablation of ATF5 negatively affected this response, particularly the normal elevations of ISR, UPR mt and antioxidant proteins.