Hedgehog Signaling in Duchenne Muscular Dystrophy
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Date
2014-12
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The Ohio State University
Abstract
Duchenne muscular dystrophy (DMD) is a severe and lethal early childhood muscle disorder. It is due to genetic mutations in the DMD gene that disrupt dystrophin protein expression in all striated muscles. As a result of loss of dystrophin, skeletal muscles undergo cycles of degeneration and chronic inflammation. Skeletal muscle normally has the ability to regenerate and repair itself. However, in DMD, muscle regeneration progressively fails leading to a loss of muscle mass and hence, muscle function. The mechanisms involved in this progressive failure of muscle regeneration are not fully understood. However, they appear tightly linked to a parallel progressive increase in fibrotic tissue that gradually replaces functional muscle tissue. Understanding the molecular mechanisms that lead to the progressive loss of muscle function is essential because it can reveal new treatment opportunities to halt disease progression and prolong lifespan in these patients.
Towards this goal, our laboratory has been studying the effects of the muscle environment on the fate choices of interstitial muscle stem cells. These stem cells have the unique ability to differentiate into muscle thus contributing to regeneration, or into fibrotic cells, thus potentially shifting the balance toward fibrosis. We have previously shown that the dystrophic muscle environment blocks the myogenic differentiation of interstitial stem cells and instead promotes their differentiation into fibrotic lineages (Penton et al., PLoS ONE, 2013). We discovered that myogenic differentiation of interstitial stem cells is dependent upon active Hedgehog signalling and that the dystrophic muscle environment inhibits Hedgehog signalling in these stem cells. Because Hedgehog signalling has not been studied in muscle disease, this thesis focuses on defining the broader role of this signalling pathway in disease progression in DMD, using the well-established mdx mouse model of DMD. We treated dystrophic mdx mice in vivo with a specific Hedgehog activator in order to restore Hedgehog signalling in dystrophic muscles to wild type levels. Short term treatment (1 week) significantly improved muscle regeneration. Interestingly, we found that inflammation was decreased along-side the regenerative effects. Long-term treatment (2 months) of mdx mice with the Hedgehog agonist lead to a decrease in fibrosis and a significant improvement in motor function.
We show for the first time that Hedgehog signalling is impaired in muscular dystrophy and that this contributes to disease progression. Our results also indicate that sustained pharmacological activation of Hedgehog signalling to wild type levels has positive effects on regeneration, inflammation, fibrosis and motor function. Further research is needed to better understand the cellular and molecular mechanisms involved in Hedgehog signalling and to identify Hedgehog inhibitors present in dystrophic muscle. This may reveal new potential targets for therapeutic intervention in muscular dystrophy.
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Keywords
hedgehog, DMD, Duchenne muscular dystrophy, muscle, signalling