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Published 1 April 2002. doi:10.1083/jcb.200108071
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© The Rockefeller University Press, 0021-9525/2002/4/137 $5.00
The Journal of Cell Biology, Volume 157, Number 1, April 1, 2002 137-148

Article

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

Elisabeth R. Barton1, Linda Morris1, Antonio Musaro2, Nadia Rosenthal3 and H. Lee Sweeney1

1 Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104
2 University of Rome "La Sapienza, " Department of Histology and Medical Embryology, 00161 Roma, Italy
3 Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129

Address correspondence to H. Lee Sweeney, Department of Physiology, B400 Richards Building, 3700 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104. Tel.: (215) 898-8725. Fax.: (215) 573-2273. E-mail: lsweeney{at}mail.med.upenn.edu

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.

Key Words: IGF-I; muscular dystrophy; satellite cells; regeneration; protein kinase B


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