YAP Acts as a Negative Regulator of Mini Utrophin-Based Gene Therapy for Duchenne Muscular Dystrophy in Mdx Mice.

Abstract

Duchenne muscular dystrophy (DMD) is a fatal rare disease caused by dystrophin deficiency, with no effective clinical treatments available to date. Using mdx mice as a model, this study investigated the therapeutic efficacy and interaction of mini utrophin (a truncated utrophin) and Yes-associated protein (YAP) delivered via recombinant adeno-associated virus (rAAV). Results showed that mini utrophin was efficiently expressed in mdx mouse skeletal muscle, significantly increased phosphorylated YAP (p-YAP) levels, restored the expression of dystrophin-glycoprotein complex (DGC) components (α/γ-sarcoglycans), reduced serum creatine kinase (CK) leakage, alleviated pathological damages such as central nucleation and inflammatory infiltration, and comprehensively improved grip strength, treadmill endurance, and pole climbing ability in mice. However, the co-overexpression of YAP completely antagonized these therapeutic effects, resulting in no improvement in pathological phenotypes or motor function of mdx mice. This study confirms that mini utrophin can effectively reverse DMD-related phenotypes, while excessive YAP activation abrogates its therapeutic efficacy, suggesting that precise regulation of YAP activity is required in DMD treatment and providing experimental basis for optimizing gene therapy strategies.