Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice

J Cell Biol. 2002 Apr 1;157(1):137-48. doi: 10.1083/jcb.200108071. Epub 2002 Apr 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Diaphragm / pathology
  • Diaphragm / physiology
  • Dystrophin / genetics
  • Fibrosis
  • Genetic Therapy*
  • Insulin-Like Growth Factor I / genetics*
  • Male
  • Mice
  • Mice, Inbred mdx
  • Mice, Transgenic
  • Muscular Dystrophy, Animal / pathology
  • Muscular Dystrophy, Animal / physiopathology*
  • Muscular Dystrophy, Animal / therapy*
  • Necrosis
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Regeneration


  • Dystrophin
  • Proto-Oncogene Proteins
  • Insulin-Like Growth Factor I
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt