The role of TFE3 in mediating skeletal muscle mitochondrial adaptations to exercise training.

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.