Impaired PGC-1 alpha function in muscle in Huntington's disease

作者：Chaturvedi Rajnish K^*; Adhihetty Peter; Shukla Shubha; Hennessy Thomas; Calingasan Noel; Yang Lichuan; Starkov Anatoly; Kiaei Mahmoud; Cannella Milena; Sassone Jenny; Ciammola Andrea; Squitieri Fernando; Beal M Flint

来源：Human Molecular Genetics, 2009, 18(16): 3048-3065.

DOI：10.1093/hmg/ddp243

We investigated the role of PPAR gamma coactivator 1 alpha (PGC-1 alpha) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1 alpha and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor beta-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1 alpha. Treatment with GPA resulted in increased expression of AMPK, PGC-1 alpha 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-1 alpha, PGC-1 beta and oxidative fibers. Oxygen consumption, PGC-1 alpha, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1 alpha expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1 alpha resulted increased expression of PGC-1 alpha and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1 alpha plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1 alpha function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.

• 出版日期2009-8-15