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The Correlation Between Tfeb and PGC‐1α in Skeletal Muscle

Muscle health is strongly dependent on the maintenance of functional mitochondria for the provision of ATP through oxidative phosphorylation. The mitochondrial pool is governed by two competing processes: mitochondrial biogenesis and autophagy (mitophagy). Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) is the master regulator of mitochondrial biogenesis, while transcription factor EB (Tfeb) regulates lysosomal biogenesis and is required for autophagy. Since the two processes are strongly linked, we sought to study their ability to regulate one another. The purpose of this study was to further elucidate the relationship between Tfeb and PGC‐1α by investigating Tfeb family members, as well as its transcription factors and downstream targets. Protein levels of Tfeb were reduced by 70% in whole body PGC‐1α KO mice compared to their WT counterparts. In contrast, muscle‐specific overexpression of PGC‐1α resulted in a 25% increase in Tfeb protein expression. Tfe3, a family member of Tfeb, was reduced by 50% in PGC‐1α KO mice. Despite this similar reduction in Tfeb and Tfe3 in KO animals, there were no significant changes observed in YY1, a transcription factor upstream of Tfeb that may regulate Tfeb expression. Since Tfeb is involved in lysosomal biogenesis, markers of chaperone‐mediated autophagy, were measured in the PGC‐1α WT and KO mice in order to see if they were affected by PGC‐1α‐mediated Tfeb downregulation. However, no changes were observed in Hsc70 or Lamp‐2A between the two genotypes. Our findings confirm the positive correlation between the two master regulators of biogenesis and autophagy, PGC‐1α and Tfeb. PGC‐1α does not seem to have an effect on markers of chaperone‐mediated autophagy, despite its regulation of Tfeb expression. Thus, it is probable that this correlation is working to promote other forms of autophagy, as well as mitochondrial biogenesis, in order regulate the turnover of the mitochondrial network.