The Role of ATF4 in Mediating Skeletal Muscle Function in Response to Acute Contractile Activity

To maintain homeostatic conditions under cellular stress, mitochondria possess the ability to initiate a nuclear retrograde signaling response to counteract the initial stressor and restore optimal organellar functioning. The Integrated Stress Response (ISR) is a newfound mitochondrial quality control stress mechanism that is activated in the face of intraorganellar stress and is capable of transducing various transcriptional responses in a manner dependent on the activating transcription factor 4 (ATF4). Mitochondrial homeostatic conditions can be challenged by acute contractile activity/exercise, activating the ISR. Using a mouse model, we sought to determine the responsiveness of the ISR and ATF4 to acute contractile activity of hindlimb muscle. Our data suggest that both the ISR and its effector, ATF4, are activated with contractile activity-induced stress at various stages. However, the precise mitochondrial stress that occurs with contractile activity and leads to the activation of the ISR and ATF4, remains to be elucidated.