Anti-fibrotic Approach Ameliorates Muscle Pathology in FSHD Animal Model

Abstract

Facioscapulohumeral Muscular Dystrophy (FSHD) stands out as one of the most prevalent forms of muscular dystrophy. Central to its pathogenesis is the misexpression of the DUX4 gene within skeletal muscle, triggering a cascade of molecular and cellular events that lead to progressive muscle weakness. The hallmark histological features of affected muscles include myofiber loss, immune cell infiltration, and deposition of fat and fibrous tissue. This excessive accumulation of collagenous extracellular matrix disrupts muscle physiology, diminishes regenerative capacity, and fosters dystrophic outcomes. Hence, our study aims to evaluate the potential therapeutic approach of targeting fibroadipogenic processes in DUX4-affected muscles. We investigated the effects of several antifibrotic drugs, known for their efficacy in acute muscle injury models, using a doxycycline-regulated DUX4-expressing FSHD mouse model. iDUX4pA;HSA mice were induced with low levels of doxycycline to express barely detectable DUX4 in myofibers and promote moderate muscle injury similar to that observed in patients. The effectiveness of the drugs was evaluated based on the severity of muscle damage, regeneration, and fibrosis at 3 weeks of treatment. Our findings revealed one drug that moderately improved muscle composition, evidenced by increased myofiber size and enhanced muscle regeneration. Treated mice exhibited reduced infiltration of fibroadipogenic (FAPs) and macrophages in affected muscles. Furthermore, the expression of genes associated with fibrosis and inflammation was diminished, supporting the beneficial effect of the drug. In conclusion, our study sheds light on the potential benefits of antifibrotic drug treatment in mildly DUX4-affected muscle in a DUX4-based FSHD animal model.