New Findings
What is the central question of this study?
Peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) gene transfer as a treatment for Duchenne muscular dystrophy is efficacious even with advanced disease.
What is the main finding and its importance?
PGC‐1α pathway activation strategies may be most effective when initiated at the earliest possible time.
Duchenne muscular dystrophy is a progressive and fatal muscle wasting disease caused by a dystrophin deficiency. We previously found that gene transfer of peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) increased abundance of utrophin and increased mitochondrial biogenesis using prevention and rescue treatment protocols. 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 mdx mice from our colony were injected in one hindlimb with a virus driving expression of PGC‐1α, while the contralateral limb was injected with empty capsid. Three months after viral gene transfer, PGC‐1α expression was 40‐fold greater than in contralateral limbs. Specific tension was increased by ∼60% (P < 0.05), and force produced during the final contraction of a fatigue protocol was 60% greater in treated soleus muscles compared with contralateral control muscles (P < 0.05). Histopathology was not improved by PGC‐1α overexpression. Also, while there were numerous differences in gene expression between healthy and dystrophic muscle, there were relatively few differences between PGC‐1α‐treated limbs and contralateral control limbs. These data indicate that PGC‐1α pathway activation may interrupt the disease process even if initiated within the context of advanced disease; however, the mechanism that underlies this functional correction is not apparent.