Muscular dystrophy: from mouse models to small molecule therapies

Muscular dystrophy (MD) is a group of genetic diseases that primarily affects the muscular tissue and is characterized by progressive muscle wasting and weakness. MDs can be classified according to the age of onset, clinical symptoms, and the mutated genes with their respective encoded proteins. According to the age of onset, MDs are divided into congenital muscular dystrophies presenting early onset at birth or within the first six months of life, and late-onset muscular dystrophies characterized by the onset after the first years of life. Currently, there is no cure or effective treatment to prevent muscular dystrophy disease progression. In this dissertation, we characterized the cardiac function in humans and a mouse model of integrin α7-related congenital muscular dystrophy (ITGA7-CMD), a rare type of congenital muscular dystrophy, and verified the loss of integrin α7 is associated with late-onset cardiomyopathy in ITGA7-CMD patients and Itga7-/- mouse model. Additionally, we investigated the efficacy of two FDA-approved small molecule drugs, sunitinib and vemurafenib, for the treatment of Duchenne muscular dystrophy (DMD) and laminin-α2-related congenital muscular dystrophy (LAMA2-CMD), respectively. Our results show that treatment with sunitinib prevents DMD-related cardiomyopathy progression by improving cardiac histopathology and function in a mouse model of DMD, and treatment with vemurafenib improves skeletal muscle histopathology by regulating fibrosis and metabolism in a mouse model of LAMA2-CMD. Together our results highlight the importance of using animal models to understand the molecular mechanisms of the disease and develop new therapies for different types of MDs