Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
J Appl Physiol (1985). 2024 Feb 1;136(2):262-273. doi: 10.1152/japplphysiol.00484.2023. Epub 2023 Dec 14.
Transcription factor E3 (TFE3) is a transcription factor that activates the expression of lysosomal genes involved in the clearance of dysfunctional mitochondria, termed mitophagy. With exercise, TFE3 is presumed to optimize the mitochondrial pool through the removal of organelles via lysosomes. However, the molecular mechanisms of the involved pathways remain unknown. Wild-type (WT) and TFE3 knockout (KO) mice were subjected to 6 wk of voluntary wheel running as an endurance training regimen. This was followed by a 45-min bout of in situ stimulation of the sciatic nerve innervating hindlimb muscles to evaluate muscle fatigue and contractile properties. A subset of animals was treated with colchicine to measure autophagy and mitophagy flux. Fatigability during stimulation was reduced with training in WT animals, as seen by a 13% increase in the percentage of maximum force at 5 min of stimulation, and a 30% increase at 30 minutes. Permeabilized fiber oxygen consumption was also improved with training. Concurrent with improved muscle and mitochondrial function, cytochrome oxidase (COX) activity and COX I protein expression were increased in trained WT animals compared to untrained animals, signifying an increase in mitochondrial content. These training adaptations were abolished with the loss of TFE3. Surprisingly, the absence of TFE3 did not affect lysosomal content nor did it blunt the induction of mitophagy flux with contractile activity compared to WT mice. Our results suggest that the loss of TFE3 compromises beneficial training adaptations that lead to improved muscle endurance and mitochondrial function. Our understanding of the role of transcription factor E3 (TFE3) in skeletal muscle is very limited. This research shows that TFE3 plays a direct role in skeletal muscle mitochondrial enhancement with exercise training, thereby introducing a paradigm shift in our perception of the function of TFE3 in mitochondrial maintenance, beyond mitophagy. This research serves to introduce TFE3 as a protein that holds promise as a future therapeutic target for metabolic diseases and skeletal muscle dysfunction.
转录因子 E3（TFE3）是一种转录因子，可激活参与清除功能失调线粒体的溶酶体基因的表达，称为线粒体自噬。通过运动，TFE3 被认为通过溶酶体去除细胞器来优化线粒体池。然而，涉及途径的分子机制尚不清楚。野生型（WT）和 TFE3 敲除（KO）小鼠接受 6 周的自愿轮跑作为耐力训练方案。随后，对支配后肢肌肉的坐骨神经进行 45 分钟的原位刺激，以评估肌肉疲劳和收缩特性。一部分动物用秋水仙碱处理以测量自噬和线粒体自噬通量。在 WT 动物中，训练可降低刺激期间的疲劳性，表现为刺激 5 分钟时最大力的百分比增加 13%，刺激 30 分钟时增加 30%。训练还改善了通透性纤维的耗氧量。与肌肉和线粒体功能的改善同时发生的是，与未经训练的动物相比，训练后的 WT 动物的细胞色素 c 氧化酶（COX）活性和 COX I 蛋白表达增加，表明线粒体含量增加。这些训练适应性在 TFE3 缺失的情况下被消除。令人惊讶的是，与 WT 小鼠相比，TFE3 的缺失既不影响溶酶体含量，也不抑制收缩活性诱导的线粒体自噬通量。我们的结果表明，TFE3 的缺失损害了导致肌肉耐力和线粒体功能改善的有益训练适应性。我们对转录因子 E3（TFE3）在骨骼肌中的作用的了解非常有限。这项研究表明，TFE3 在运动训练中直接作用于骨骼肌线粒体增强，从而改变了我们对 TFE3 在维持线粒体中的作用的认识，超出了线粒体自噬。这项研究将 TFE3 作为一种蛋白质引入，该蛋白质有望成为代谢疾病和骨骼肌功能障碍的未来治疗靶点。
