PGC‐1α gene transfer rescues dystrophic muscle from advanced disease progression (884.18)

Abstract

Duchenne muscular dystrophy (DMD) is a progressive, fatal, muscle wasting disease caused by a dystrophin deficiency. The benefits of exercise for DMD patients are unclear and advanced disease progression may limit exercise capacity. We found previously that gene transfer of the exercise mimetic, PGC‐1α, increased abundance of utrophin as well as increased mitochondrial biogenesis using prevention and rescue paradigms. It is well accepted that increased abundance of the dystrophin‐related protein, utrophin, serves as an adequate substitute for dystrophin in dystrophic skeletal muscle. Our purpose in this investigation was to determine the extent to which PGC‐1α gene transfer would rescue dystrophic muscle following prolonged disease progression. One year old male mdx mice from our colony were injected in one hind limb with a virus driving expression of PGC‐1α while the contralateral limb was injected with empty capsid. Following three months of treatment we found that virus caused a 5‐fold increase in PGC‐1α expression in the gastrocnemius. Muscle function was measured in the soleus, in vitro. Muscle weight, tetanic force, and cross sectional area were similar between groups. Soleus muscles over‐expressing PGC‐1α increased specific tension by approximately 60% (p<0.05) and were more resistant to fatigue when stimulated over the course of 10 minutes (p<0.05). Force produced during the final contraction was 60% greater in treated soleus muscles than control (p<0.05). These data indicate that PGC‐1α pathway activation may interrupt the disease process even if initiated within the context of advanced disease. Supported in part by CIAG and Physiological Assessment Core of the Wellstone Muscular Dystrophy Cooperative Center at the University of Pennsylvania.Grant Funding Source: CIAG