PGC-1alpha is a transcriptional coactivator promoting oxidative metabolism in many tissues. Its expression in skeletal muscle (SKM) is induced by hypoxia and reactive oxidative species (ROS) generated during exercise, suggesting that PGC-1alpha might mediate the crosstalk between oxidative metabolism and cellular responses to hypoxia and ROS. Here we found that PGC-1alpha directly interacted with Bhlhe40, a bHLH transcriptional repressor induced by hypoxia and protects SKM from ROS damage, and they co-occupied PGC-1alpha targeted gene promoters/enhancers, which in turn repressed PGC-1alpha transactivational activity. Bhlhe40 repressed PGC-1alpha activity through recruiting HDACs and preventing the relief of PGC-1alpha intra-molecular repression caused by its own intrinsic suppressor domain. Knockdown of Bhlhe40 mRNA increased levels of ROS, fatty acid oxidation, mitochondria DNA, and the expression of PGC-1alpha target genes. Similar effects were also observed when the Bhlhe40 mediated repression was rescued by a dominantly active form of the PGC-1alpha-interacting domain (PID) from Bhlhe40. We further found that Bhlhe40 mediated repression can be largely relieved by exercise, in which its recruitment to PGC-1alpha targeted cis-elements were significantly reduced. These observations suggest that Bhlhe40 is a novel regulator of PGC-1alpha activity repressing oxidative metabolism gene expression and mitochondrion biogenesis in sedentary SKM.
Date:
2015-07
Relation:
Molecular and Cellular Biology. 2015 Jul;35(14):2518-2529.
