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

Abstract

We investigated the role of PPAR gamma coactivator 1alpha (PGC-1alpha) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1alpha 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-1alpha. Treatment with GPA resulted in increased expression of AMPK, PGC-1alpha 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-1alpha, PGC-1beta and oxidative fibers. Oxygen consumption, PGC-1alpha, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1alpha expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1alpha resulted increased expression of PGC-1alpha and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1alpha plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1alpha function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.

HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation

“…To identify gene expression changes associated with altered histone acetylation levels, we performed microarray analysis on skeletal muscle samples from N171-82Q HD transgenic mice treated with the HDAC1/3-targeting compound HDACi 4b and reanalyzed microarray data from brain samples of HDACi 4b-treated R6/2 transgenic mice from our earlier studies (11). We used skeletal muscle in light of the fact that many reports have implicated skeletal muscle dysfunction as an important factor in motor dysfunction, both in human and animal HD models (17)(18)(19)(20). Using two pathway analysis programs, Ingenuity Systems Pathway Analysis (Ingenuity Systems) and Database for Annotation, Visualization, and Integrated Discovery (DAVID), we found that gene expression alterations in response to HDACi 4b treatment were significantly associated with DNA methylation and chromatin organization (Tables S1 and S2).…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…This wasting phenotype could be improved by artificially increasing PGC-1 levels in skeletal muscle [145].…”

Consequences of Mitochondrial Dysfunction in Huntington's Disease and Protection via Phosphorylation Pathways

“…The levels of PGC-1alpha and Tfam were found to be reduced in HD Chaturvedi et al 2009). Moreover, both proteins have been reported to be significantly reduced in brain lysates from HD patients, which was correlated with HD progression (Kim et al 2010).…”

“…Interestingly, decreased expression of PGC1alpha was observed in MSNs (largely affected in HD), whereas striatal interneurons showed increased mRNA levels for PGC-1alpha which could, at least partially, explain the different vulnerability of these striatal neuronal populations. PGC-1alpha and Tfam were also reduced in muscle biopsies and myoblast cultures from HD subjects (Chaturvedi et al 2009). Transcriptional repression of PGC-1alpha by mHtt leads not only to mitochondrial dysfunction, but also to neurodegeneration, suggesting a key role for PGC-1alpha in the control of energy metabolism in the early stages of HD pathogenesis .…”