RESUMO
Duchenne muscular dystrophy is typically diagnosed in the preschool years because of locomotor defects, indicative of muscle damage. Thus, effective therapies must be able to rescue muscle from further decline. We have established that peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α) gene transfer will prevent many aspects of dystrophic pathology, likely through upregulation of utrophin and increased oxidative capacity; however, the extent to which it will rescue muscle with disease manifestations has not been determined. Our hypothesis is that gene transfer of Pgc-1α into declining muscle will reduce muscle injury compared with control muscle. To test our hypothesis, adeno-associated virus 6 (AAV6) driving expression of Pgc-1α was injected into single hind limbs of 3-wk-old mdx mice, while the contralateral limb was given a sham injection. At 6 wk of age, treated solei had 37% less muscle injury compared with sham-treated muscles (P < 0.05). Resistance to contraction-induced injury was improved 10% (P < 0.05), likely driven by the five-fold (P < 0.05) increase in utrophin protein expression and increase in dystrophin-associated complex members. Treated muscles were more resistant to fatigue, which was likely caused by the corresponding increase in oxidative markers. Pgc-1α overexpressing limbs also exhibited increased expression of genes related to muscle repair and autophagy. These data indicate that the Pgc-1α pathway remains a good therapeutic target, as it reduced muscle injury and improved function using a rescue paradigm. Further, these data also indicate that the beneficial effects of Pgc-1α gene transfer are more complex than increased utrophin expression and oxidative gene expression.