ATF5 is Required For The Normal Stress Response in Skeletal Muscle During Denervation

Chronic muscle disuse induces a plethora of negative physiological processes such as significant muscle atrophy, a decrease in mitochondrial content and an increase in organelle dysfunction. The main line of defence in response to these abnormalities includes the Integrated Stress Response (ISR) and the Mitochondrial Unfolded Protein Response (UPR mt ). These pathways aim to restore cellular homeostasis by reducing global protein synthesis while simultaneously activating specific transcription factors such as ATF5 to induce changes in gene expression. The objective of the current study is to better characterize the possible regulatory role of ATF5 on the UPR mt during mitochondrial stress brought about by chronic muscle disuse, induced by denervation. ATF5 KO male and female mice were confirmed via DNA genotyping based on the presence of the mutant ATF5 gene and the absence of the WT gene. Unilateral denervation was induced in the lower limb via sectioning of the sciatic nerve. The opposing limb was sham-operated. After 7 days, mice were sacrificed and the tibialis anterior (TA) and gastrocnemius (GAS), were snap frozen in liquid nitrogen and stored at -80C for future experimentation. TA muscle was used for western blotting, while GAS muscle was used for COX activity analysis to assess mitochondrial content. Denervation resulted in a significant decrease in normalized muscle mass in all hindlimb muscle groups regardless of sex or genotype. These results were supported by the significant increase in total P62, LC3I/II, and Beclin1 protein levels in WT animals. However, this mitophagy/autophagy response was blunted in the ATF5 KO model. ISR activation was confirmed by significant increases in ATF4, CHOP and total eIF2α protein levels in WT animals. Likewise, the response of CHOP and eIF2α was significantly reduced in the absence of ATF5. Basal protein levels of various mitochondrial chaperones and proteases were modestly elevated in the ATF5 KO model. However, the UPR mt response of LONP1, HSP60, and CPN10 was impaired in ATF5 KO mice following denervation. Interestingly, antioxidant protein NQO1 was significantly lower in ATF5 KO mice compared to WT controls. Mitochondrial content, estimated using COX activity, was higher in the absence of ATF5 in both SHAM and DEN conditions compared to WT mice, but was reduced similarly by denervation. In conclusion, the lack of ATF5 appears to negatively affect the normal mitophagy/autophagy response along with the ISR/UPR mt in the presence of denervation. Thus, ATF5 appears to be necessary to maintain anti-oxidant capacity as well as to induce the normal compensatory stress response associated with the mitochondrial dysfunction that accompanies muscle denervation. Supported by NSERC Canada This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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