PGC‐1α – Dependent TFEB Expression and Activation with Exercise

A functional mitochondrial network is required for the maintenance of healthy skeletal muscle, and this is controlled by the opposing processes of mitochondrial biogenesis and mitophagy. The coactivator PGC‐1a regulates the synthesis of new mitochondria, while the coordinated transcription of lysosomal and autophagy‐related genes is controlled by transcription factor EB (TFEB). PGC‐1a activation and expression are induced with exercise, leading to a subsequent increase in mitochondrial biogenesis. However, the effect of exercise on TEFB expression and activation has yet to be elucidated. Since biogenesis and mitophagy are closely linked, the purpose of our study was to investigate the interplay between PGC‐1a and TFEB in maintaining mitochondrial homeostasis in response to chronic contractile activity in C2C12 myotubes, and following acute treadmill exercise in WT and PGC‐1a KO mice. In C2C12 cells, TFEB nuclear localization was increased by 1.6‐fold following 2 hours of acute, electrical stimulation‐induced contractile activity. Cells transfected with a 1600 bp TFEB promoter‐reporter construct revealed that TFEB transcription was simultaneously increased by 3‐fold by contractile activity. To evaluate this in vivo , WT and KO mice were subjected to acute treadmill exercise. In WT mice, TFEB translocation to the nucleus increased 2.4‐fold. In contrast, KO mice exhibited no increases in TFEB translocation with exercise, yet showed a 4‐fold increase in mTOR activation. This suggests an increased phosphorylation and inhibition of TFEB in KO muscle following exercise. In addition, TFEB transcription, assessed through the intramuscular electroporation of the TFEB promoter‐reporter construct, was elevated by 4‐fold in response to exercise. This transcriptional response to exercise was completely abolished in the KO mice. TFEB protein levels were also reduced by 30% in the KO mice compared to their WT counterparts, however no changes were observed in most of the downstream targets of TFEB transcription. mRNA levels of the mitochondrial marker COXI were reduced by 47% in KO mice compared to WT counterparts basally, while exercise induced a 33–38% elevation in both genotypes. Furthermore, both WT and KO mice exhibited and 50% decrease in the mRNAs encoding autophagy genes. Our data suggest that acute exercise provokes TFEB expression and activation both in vitro and in vivo, in a PGC‐1a‐dependent manner. PGC‐1a controls expression of TFEB with exercise likely via transcriptional mechanisms. Furthermore, ablation of PGC‐1a seems to play a role in increased TFEB inhibition via mTOR phosphorylation, indicating a more complex role for PGC‐1a in mediating TFEB expression, as well as function. Support or Funding Information This work is supported by the Natural Science and Engineering Research Council (NSERC) of Canada.

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