Myostatin Propeptide Gene Delivery by Adeno-Associated Virus Serotype 8 Vectors Enhances Muscle Growth and Ameliorates Dystrophic Phenotypes in mdx Mice

摘要

Myostatin has been extensively documented as a negative regulator of muscle growth. Myostatin inhibition isntherefore considered an attractive strategy for the treatment of muscle-wasting diseases such as muscular dystrophies.nTo investigate whether systemic gene delivery of myostatin propeptide (MRPO), a natural inhibitornof myostatin, could enhance body-wide skeletal muscle growth, we used adeno-associated virus serotypen8 (AAV8) vectors to deliver the MRPO gene into either normal mice or mdx mice, a murine model of Duchennenmuscular dystrophy (DMD). In normal mice, a significant increase in skeletal muscle mass was observed afterneither an intraperitoneal injection of AAV-MPRO into neonates, or an intravenous injection of AAVMPRO76AFcn(a modified MPRO fused with IgG Fc) into adults. Enhanced muscle growth occurred becausenof myofiber hypertrophy, not hyperplasia. In mdx mice, a significant increase in skeletal muscle mass was alsonobserved after AAV-MPRO76AFc injection. The treated mdx mice showed larger and more uniform myofibers,nfewer infiltrating mononuclear cells, less fibrosis, and lower serum creatine kinase levels. In addition,na grip force test and an in vitro tetanic contractile force test showed improved muscle strength. A treadmillntest, however, showed reduced endurance of the treated mdx mice compared with their untreated counterparts.nImportantly, no cardiac hypertrophy was observed in either normal or mdx mice after myostatin inhibitionnby gene delivery. These results clearly demonstrate the efficacy of AAV8-mediated myostatin propeptidengene delivery in a rodent model of DMD, and warrant further investigation in large animal models andneventually in human patients.