Exercise induces TFEB expression and activity in skeletal muscle in a PGC-1α-dependent manner

The mitochondrial network in muscle is controlled by the opposing processes of mitochondrial biogenesis and mitophagy. The coactivator peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) regulates biogenesis, while the transcription of mitophagy-related genes is controlled by transcription factor EB (TFEB). PGC-1 alpha activation is induced by exercise; however, the effect of exercise on TFEB is not fully known. We investigated the interplay between PGC-1 alpha and TFEB on mitochondria in response to acute contractile activity in C2C12 myotubes and following exercise in wild-type and PGC-1 alpha knockout mice. TFEB nuclear localization was increased by 1.6-fold following 2 h of acute myotube contractile activity in culture, while TFEB transcription was also simultaneously increased by twofold to threefold. Viral overexpression of TFEB in myotubes increased PGC-1 alpha and cytochrome-c oxidase-IV gene expression. In wild-type mice, TFEB translocation to the nucleus increased 2.4-fold in response to acute exercise, while TFEB transcription, assessed through the electroporation of a TFEB promoter construct, was elevated by fourfold. These exercise effects were dependent on the presence of PGC-1 alpha. Our data indicate that acute exercise provokes TFEB expression and activation in a PGC-1 alpha dependent manner and suggest that TFEB, along with PGC-1 alpha, is an important regulator of mitochondrial biogenesis in muscle as a result of exercise.