The Role of TFEB and TFE3 in Mediating Mitochondrial and Lysosomal Adaptations in Skeletal Muscle

Skeletal muscle adapts to external stimuli to meet metabolic and energetic needs imposed on it. As a highly metabolic tissue, mitochondria are the energetic cores of the cell and are central to the adaptive nature of muscle. Essential to the maintenance of mitochondria is the process of mitophagy, a selective form of autophagy through which damaged mitochondria are removed and degraded via the lysosome. Lysosomes and autophagy machinery are regulated by transcription factors, TFEB and TFE3, that are responsive to cellular stresses including exercise, disuse and starvation. Our work aimed to address the role of TFEB and TFE3 in mediating the adaptability of mitochondria in response to exercise and disuse. To understand the role of TFEB and TFE3 in mediating the effects of exercise, we employed an in vitro model and silenced the expression of TFEB and TFE3. While the absence of TFEB or TFE3 alone impacted the mitophagic response to a single bout of contractile activity, mitochondrial and lysosomal function improved with repeated bouts. These data support the notion that exercise stimulates multifaceted and often redundant signaling pathways to promote adaptations. However, the absence of TFEB and TFE3 together abolished functional mitochondrial and lysosomal adaptations to contractile activity, indicating that both TFEB and TFE3 together are required for adaptations. We also sought to evaluate the role of TFE3 in atrophic conditions using denervation of the sciatic nerve as a model of disuse in both males and females. Basally, females exhibited increased lysosomal content, higher mitophagy flux and improved mitochondrial function. In response to denervation however, females appeared to preferentially preserve mitochondrial content at the expense of function by reducing mitophagy flux. Curiously, the absence of TFE3 in vivo preserved muscle mass in males and mitochondrial content in both sexes following denervation but this in turn increased mitochondrial dysfunction similar to wildtype females. The significance of this work is that we provide further evidence of how lysosomes and mitochondrial turnover mediate mitochondrial adaptations to both positive and negative stimuli. Our data also highlight the importance of investigating the effect of biological sex, revealing distinct mitochondrial and lysosomal phenotypes in males and females.