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PGC‐1α over‐expression rescues dystrophin‐deficient skeletal muscle
Author(s) -
GardanSalmon Delphine,
Hollinger Katrin,
Santana Connie,
Selsby Joshua T
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1051.33
Subject(s) - dystrophin , utrophin , duchenne muscular dystrophy , skeletal muscle , hindlimb , transgene , mdx mouse , genetic enhancement , medicine , eccentric , endocrinology , myopathy , genetically modified mouse , inflammation , biology , gene , genetics , physics , quantum mechanics
Utrophin replacement has shown great promise as a therapy for DMD, however, a practical means of delivery in human patients is lacking. PGC‐1α has been shown to increase utrophin and expression of oxidative proteins, which may be of additional benefit to dystrophic muscle. Previously, transgenic PGC‐1α over‐expression prevented the typical phenotypic decline in mdx mice. Further, we have shown that neonatal PGC‐1α induction blunted acute eccentric injury in mdx mice. As boys are generally diagnosed following disease onset it is imperative to determine the extent to which PGC‐1α over‐expression can rescue skeletal muscle with active disease pathology. Three week old mdx mice were injected in the left hind limb with null AAV6 and in the right hind limb with an AAV6 driving expression of PGC‐1α (1x10^11 gc). At six weeks of age, mice were euthanized and muscles removed. PGC‐1α over‐expression reduced total damaged area by 37% (p<0.05). More specifically, the areas of hypercontracted cells, immune cell infiltration, and missing cells were reduced by 65%, 31%, and 43%, respectively (p<0.05). These data indicate that PGC‐1α gene transfer following postnatal development of the disease can confer a high degree of improvement to dystrophic muscle. This investigation justifies further exploration of PGC‐1α as a potential avenue for treating patients with DMD. Partially supported by CIAG.