Impaired PGC-1a function in muscle in Huntington’s disease

We investigated the role of PPAR g coactivator 1a (PGC-1a) in muscle dysfunction in Huntington’s disease (HD). We observed reduced PGC-1a and target genes expression in muscle of HD transgenic mice. We pro-duced chronic energy deprivation in HD mice by administering the catabolic stressor b-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1a. Treatment with GPA resulted in increased expression of AMPK, PGC-1a target genes, genes for oxidative phosphorylation, electron transport chain and mitochondrial biogenesis, increased oxidative muscle fibers, numbers of mitochondria and motor performance in wild-type, but not in HD mice. In muscle biopsies from HD patients, there was decreased PGC-1a, PGC-1b and oxidative fibers. Oxygen consumption, PGC-1a, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1a expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1a resulted increased expression of PGC-1a and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1a plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1a function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions