Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice.
Duchenne muscular dystrophy is an X-linked degenerative disorder of muscle caused by the absence of the protein dystrophin. A major consequence of muscular dystrophy is that the normal regenerative capacity of skeletal muscle cannot compensate for increased susceptibility to damage, leading to repetitive cycles of degeneration-regeneration and ultimately resulting in the replacement of muscle fibers with fibrotic tissue. Because insulin-like growth factor I (IGF-I) has been shown to enhance muscle regeneration and protein synthetic pathways, we asked whether high levels of muscle-specific expression of IGF-I in mdx muscle could preserve muscle function in the diseased state. In transgenic mdx mice expressing mIgf-I (mdx:mIgf+/+), we showed that muscle mass increased by at least 40% leading to similar increases in force generation in extensor digitorum longus muscles compared with those from mdx mice. Diaphragms of transgenic mdx:mIgf+/+ exhibited significant hypertrophy and hyperplasia at all ages observed. Furthermore, the IGF-I expression significantly reduced the amount of fibrosis normally observed in diaphragms from aged mdx mice. Decreased myonecrosis was also observed in diaphragms and quadriceps from mdx:mIgf+/+ mice when compared with age-matched mdx animals. Finally, signaling pathways associated with muscle regeneration and protection against apoptosis were significantly elevated. These results suggest that a combination of promoting muscle regenerative capacity and preventing muscle necrosis could be an effective treatment for the secondary symptoms caused by the primary loss of dystrophin.
Barton
Elisabeth R
ER
Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Morris
Linda
L
Musaro
Antonio
A
Rosenthal
Nadia
N
Sweeney
H Lee
HL
D000818:Animals; D003964:Diaphragm / Q000473:pathology / Q000502:physiology; D016189:Dystrophin / Q000235:genetics; D005355:Fibrosis; D015316:Genetic Therapy; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D009137:Muscular Dystrophy, Animal / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D009336:Necrosis; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012038:Regeneration
D016189:Dystrophin; D011518:Proto-Oncogene Proteins; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt