Interplay between Skeletal Muscle Catabolism and Remodeling of Arteriovenous Fistula via YAP1 Signaling

Background: Arteriovenous (AV) fistulas are the preferred access for dialysis but have a high incidence of failure. This study aims to understand the crosstalk between skeletal muscle catabolism and AV fistula maturation failure. Methods: Skeletal muscle metabolism and AV fistula maturation were evaluated in mice with chronic kidney disease (CKD). The roles of myostatin and YAP1 in regulating the transdifferentiation of adventitial mesenchymal stem cells (mesenchymal stem cells) and intima hyperplasia in AV fistula were investigated. Nanoparticles carrying a YAP1 inhibitor, verteporfin, with light irradiation-controlled release were synthesized and applied to AV fistula. Results: Increased trichrome signals and stenosis were observed in AV fistulas from mice treated with myostatin and from mice with CKD. In contrast, blocking myostatin function with an anti-myostatin peptibody not only improved body weight and muscle size in CKD mice but also decreased neointima formation in AV fistulas. In cultured mesenchymal stem cells, myostatin induced YAP1 expression, promoting the differentiation of mesenchymal stem cells into myofibroblasts and inducing extracellular matrix deposition. Red light irradiation-controlled release of verteporfin from nanoparticles blocked YAP1 activation and alleviated myostatin-induced mesenchymal stem cell activation. Periadventitial application and red-light irradiation of nanoparticles carrying verteporfin significantly suppressed stiffening and neointima formation in AV fistula. Conclusions: CKD induced muscle wasting leading to increased production of myostatin, which stimulated mesenchymal stem cell activation and vascular fibrosis linked to AV fistula stenosis. YAP1 signaling was activated in these processes. Red-light irradiation-controlled release of verteporfin offered a feasible approach for local vascular drug intervention to improve AV fistula maturation.