Epigenetic therapy to abrogate myostatin signalling in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) affects 1 in 3500 male births. Affected patients suffer from progressive muscle weakness and degeneration. To date there is no effective cure for DMD, although promising cellular, viral, and pharmacological approaches are under investigation for successful therapies. A newly emerged strategy to alleviate the symptoms of DMD is to increase of muscle mass (muscle hypertrophy) by inhibition of myostatin, a protein that limits muscle growth. Mice lacking myostatin show distinct muscle hypertrophy, known as “double muscling phenotype”. Myostatin blockade leads to an increase in muscle size and may ameliorate the function of the dystrophic muscle. Several research groups are attempting to reduce myostatin levels by different approaches. Our data show that a protein called BRD4 activates transcription of the myostatin gene. Recently, the BRD4 inhibitor JQ1 was developed to block BRD4 function. JQ1 treatment determines an increase in myotubes size and a decrease in myostatin levels, in a cell culture model. We will study the effect of JQ1 in a mouse model of DMD, the mdx mouse. We will evaluate whether JQ1 treatment results in an increase in myofibers size and whether JQ1 helps the restoration of muscle function in the mouse model of Duchenne muscular dystrophy. JQ1 is currently considered an anti-tumoral drug, but it may become a promising therapeutic agent to contrast muscle loss in diseases associated to muscle degeneration and wasting, as DMD.