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

RK Chaturvedi, P Adhihetty, S Shukla… - Human molecular …, 2009 - academic.oup.com
RK Chaturvedi, P Adhihetty, S Shukla, T Hennessy, N Calingasan, L Yang, A Starkov
Human molecular genetics, 2009academic.oup.com
We investigated the role of PPAR γ coactivator 1α (PGC-1α) in muscle dysfunction in
Huntington's disease (HD). We observed reduced PGC-1α 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-1α. Treatment with GPA resulted in increased expression of AMPK, PGC-1α …
Abstract
We investigated the role of PPAR γ coactivator 1α (PGC-1α) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1α 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-1α. Treatment with GPA resulted in increased expression of AMPK, PGC-1α 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-1α, PGC-1β and oxidative fibers. Oxygen consumption, PGC-1α, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1α expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1α resulted increased expression of PGC-1α and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1α plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1α function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.
Oxford University Press
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