Skeletal Muscle Health and Mitochondrial Function are Regulated By The Transcription Factor ATF5 During Aging

In skeletal muscle, the mitochondrial network is highly regulated by coordinated mitochondrial quality control (MQC) processes. The Mitochondrial Unfolded Protein Response (UPR mt ), a conserved regulatory process, is activated in response to a variety of organellar stressors. This quality control paradigm is primarily regulated by the transcription factor ATF5, in conjunction with ATF4 and CHOP. In order to sustain optimal functioning, skeletal muscle relies on a dynamic and efficient mitochondrial pool. However, with age, this mitochondrial capacity becomes impaired, demonstrated by reductions in respiration and elevations in ROS generation. These factors combined contribute to a decline in the quality of the mitochondrial pool and aberrations in muscle health. Within the context of the UPR mt , extensive literature using C.elegans has demonstrated the importance of UPR mt activation in maintaining mitochondrial health during aging and longevity, however, this relationship in mammals is unknown. In addition, whether ATF5 is required for this response has yet to be determined. To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months) ATF5 KO and WT mice. Muscle characteristics and fatigability were examined via utilization of an in situ hindlimb protocol by acutely stimulating muscles at 0.25, 0.5, and 1 tetani/per second for 9 mins. Young ATF5 KO mice showed no change in fatiguability relative to young WT mice. With age, however, ATF5 KO mice experienced greater fatiguability compared to aged-matched WT mice, suggesting that ATF5 is required to maintain muscle endurance in aging muscle. Aged WT mice showed a decline in muscle mass relative to young counterparts. Interestingly, ATF5 KO mice maintained their muscle mass with age. To supplement these findings, the expression of the muscle atrophy markers, Atrogin-1, MuRF-1, GADD45α, p21, and p53, were blunted in aged ATF5 KO mice. Unexpectedly, a subunit of the 20S Proteosome, PSMB4, was also downregulated in ATF5 KO mice regardless of age, further fortifying the mechanism responsible for the maintenance of muscle mass in the absence of ATF5. Assessment of mitochondrial respiration and ROS emission via Clark Electrode revealed reductions in mitochondrial functioning and elevations in ROS production in ATF5 KO mice, a finding that was further amplified with age. In addition, UPR mt markers revealed an age-associated reduction in the expression of mitochondrial chaperones, mtHSP70 and HSP60 and elevations in CHOP and ATF4. The absence of ATF5 increased the expression of the protease ClpP and the antioxidant NQO1, suggesting plausible elevations in mitochondrial proteotoxicity and oxidative stress, elevated with age. These data thereby suggest that ATF5 is a critical factor required to promote mitochondrial hormesis and thus skeletal muscle health with age. Future work will reveal the precise underlying mechanisms that contribute to the activation of UPR mt signaling in aging muscle. Victoria C. Sanfrancesco is the recipient of NSERC Canada Graduate Scholarship-Doctoral (CGS-D). David A. Hood is the holder of a Canadian Research Chair in Cell Physiology. 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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