Human Molecular Genetics Advance Access originally published online on May 21, 2009
Human Molecular Genetics 2009 18(16):3048-3065; doi:10.1093/hmg/ddp243
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Impaired PGC-1
function in muscle in Huntington's disease
1 Department of Neurology and Neuroscience 2 Department of Neurosurgery, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, USA 3 Neurogenetics Unit, IRCCS Neuromed, Pozzilli, Italy 4 Department of Neurology and Laboratory of Neuroscience, Dino Ferrari Center, IRCCS Auxologico Italiano, Milan, Italy
* To whom correspondence should be addressed at: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, 525 East 68th Street, F610, New York, NY 10065, USA. Email: rajnish{at}iitr.res.in and fbeal{at}med.cornell.edu
Received March 28, 2009; Accepted May 19, 2009
We investigated the role of PPAR 
coactivator 1
(PGC-1) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1 and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor β-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1. Treatment with GPA resulted in increased expression of AMPK, PGC-1 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, PGC-1β and oxidative fibers. Oxygen consumption, PGC-1, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1 expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1 resulted increased expression of PGC-1 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 plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1 function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.
Present address: Developmental Toxicology Division, Indian Institute of Toxicology Research, 80, MG Marg, Lucknow, India.