Journal or Book Title
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
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 co-activator 1-alpha (PGC-1α) gene transfer will prevent many aspects of dystrophic pathology, likely through up-regulation 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 to control muscle. To test our hypothesis AAV6 driving expression of PGC-1α was injected into single hind limbs of 3 week old mdx mice while the contralateral limb was given a sham injection. At six weeks of age treated solei had 37% less muscle injury compared to sham-treated muscles (p<0.05). Resistance to contraction induced injury was improved 10% (p<0.05) likely driven by the 5-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 over-expressing 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.
American Physiological Society
Hollinger, Katrin; Gardan-Salmon, Delphine; Santana, Connie; Rice, Drance; Snella, Elizabeth; and Selsby, Joshua T., "Rescue of dystrophic skeletal muscle by PGC-1α involves restored expression of dystrophin-associated protein complex components and satellite cell signaling" (2013). Animal Science Publications. 702.