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Evaluating the PGC-1 alpha pathway and a new preclinical model to advance treatment options for dystrophinopathies

Duchenne muscular dystrophy (DMD) is caused by a mutation in the dystrophin gene leading to the production of a nonfunctional protein and a dystrophin deficiency. Dystrophic muscle becomes progressively more necrotic and fibrotic eventually causing impaired muscle function. Patients are typically diagnosed due to the loss of muscle function indicating advanced disease, therefore successful treatments need to be able to rescue dystrophindeficient muscle from further decline. It has been demonstrated that Peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α) over-expression can prevent disease onset in mdx mice, a mouse model for DMD. As a next step, the work presented here evaluated the extent to which PGC-1α over-expression rescued dystrophic muscle during the initial bout of necrosis (three weeks of age) as well as after prolonged disease progression (one year of age). AAV6 was used to deliver the PGC-1α gene to a single hind limb while the contralateral limb was given a control injection. PGC-1α gene transfer improved muscle function and histopathology when delivered during the initial bout of necrosis. Also, beneficial changes in genes involved in dystroglycoprotein complex (DGC) assembly, oxidative metabolism, muscle repair, and autophagy were observed. While PGC-1α gene transfer following prolonged disease rescued some aspects of muscle function the cumulative effects were more modest. To increase the clinical relevance of this work the orallyavailable PGC-1α pathway activator quercetin was evaluated for its ability to mitigate histopathology in dystrophic skeletal muscle. Using a rescue paradigm prolonged quercetin supplementation led to improved histopathology and increased mitochondrial biogenesis compared to control-fed animals.