Sanfrancesco Victoria C, Hood David A
Muscle Health Research Centre, School of Kinesiology and Health ScienceYork University, Toronto, Ontario, Canada.
J Appl Physiol (1985). 2025 Mar 1;138(3):857-871. doi: 10.1152/japplphysiol.00307.2024. Epub 2024 Oct 17.
Skeletal muscle relies on mitochondria to produce energy and support its metabolic flexibility. The function of the mitochondrial pool is regulated by quality control (MQC) processes. The integrated stress response (ISR), a MQC pathway, is activated in response to various cellular stressors. The transcription factor ATF4, the main effector of the ISR, ameliorates cellular stress by upregulating protective genes, such as CHOP and ATF5. Recent literature has shown that the ISR is activated upon mitochondrial stress; however, whether this includes acute exercise-induced stress is poorly defined. To investigate this, a mouse in situ hindlimb protocol was utilized to acutely stimulate muscles at 0.25, 0.5, and 1 tetanic contraction/s for 9 min, followed by a 1-h recovery period. CAMKIIα and JNK2 were robustly activated sixfold immediately after the protocol. ISR activation, denoted as the ratio of phosphorylated to total eIF2α protein levels, was also elevated after recovery. Downstream, contractile activity induced an increase in the nuclear localization of ATF4. Robust twofold increases in the mRNA expression of ATF4 and CHOP were also observed after the recovery period. Changes in ATF4 mRNA were independent of transcriptional activation, as assessed with an ATF4 promoter-reporter plasmid. Instead, mRNA decay assays revealed an increase in ATF4 mRNA stability post contractile activity, as a result of enhanced stabilization by the RNA binding protein HuR. Thus, acute contractile activity is sufficient to induce mitochondrial stress and activate the ISR, corresponding to the induction of ATF4 with potential consequences for mitochondrial phenotype adaptations in response to repeated exercise. The integrated stress response (ISR) is a mitohormetic stress response critical for the maintenance of mitochondrial homeostasis. However, its role in mediating mitochondrial adaptations with exercise-induced stress is not well established. This research demonstrates that acute contractile activity can elicit mitochondrial stress and activate the ISR to maintain mitochondrial homeostasis via the enhancement of the functioning of ATF4, illustrating an early response to exercise that promotes mitochondrial health and adaptations.
骨骼肌依赖线粒体产生能量并支持其代谢灵活性。线粒体池的功能受质量控制（MQC）过程调节。整合应激反应（ISR）作为一种MQC途径，在应对各种细胞应激源时被激活。转录因子ATF4是ISR的主要效应因子，通过上调保护性基因（如CHOP和ATF5）来减轻细胞应激。最近的文献表明，ISR在线粒体应激时被激活；然而，这是否包括急性运动诱导的应激尚不清楚。为了研究这一点，采用小鼠原位后肢实验方案，以0.25、0.5和1次强直收缩/秒的频率对肌肉进行9分钟的急性刺激，随后有1小时的恢复期。在实验方案结束后，CAMKIIα和JNK2立即被强烈激活了6倍。ISR激活，以磷酸化eIF2α与总eIF2α蛋白水平的比值表示，在恢复后也有所升高。在下游，收缩活动导致ATF4的核定位增加。在恢复期后，还观察到ATF4和CHOP的mRNA表达强劲增加了两倍。用ATF4启动子报告质粒评估发现，ATF4 mRNA的变化与转录激活无关。相反，mRNA衰变分析显示，收缩活动后ATF4 mRNA稳定性增加，这是RNA结合蛋白HuR增强稳定作用的结果。因此，急性收缩活动足以诱导线粒体应激并激活ISR，这与ATF4的诱导相对应，可能对线粒体表型适应重复运动产生影响。整合应激反应（ISR）是一种对维持线粒体稳态至关重要的线粒体应激反应。然而，其在介导运动诱导应激下的线粒体适应中的作用尚未明确确立。这项研究表明，急性收缩活动可诱导线粒体应激并激活ISR，通过增强ATF4的功能来维持线粒体稳态，说明了对运动促进线粒体健康和适应的早期反应。
