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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 repet...

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Autores principales: Barton, Elisabeth R., Morris, Linda, Musaro, Antonio, Rosenthal, Nadia, Sweeney, H. Lee
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173262/
https://www.ncbi.nlm.nih.gov/pubmed/11927606
http://dx.doi.org/10.1083/jcb.200108071
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author Barton, Elisabeth R.
Morris, Linda
Musaro, Antonio
Rosenthal, Nadia
Sweeney, H. Lee
author_facet Barton, Elisabeth R.
Morris, Linda
Musaro, Antonio
Rosenthal, Nadia
Sweeney, H. Lee
author_sort Barton, Elisabeth R.
collection PubMed
description 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.
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spelling pubmed-21732622008-05-01 Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice Barton, Elisabeth R. Morris, Linda Musaro, Antonio Rosenthal, Nadia Sweeney, H. Lee J Cell Biol Article 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. The Rockefeller University Press 2002-04-01 /pmc/articles/PMC2173262/ /pubmed/11927606 http://dx.doi.org/10.1083/jcb.200108071 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Barton, Elisabeth R.
Morris, Linda
Musaro, Antonio
Rosenthal, Nadia
Sweeney, H. Lee
Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice
title Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice
title_full Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice
title_fullStr Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice
title_full_unstemmed Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice
title_short Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice
title_sort muscle-specific expression of insulin-like growth factor i counters muscle decline in mdx mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173262/
https://www.ncbi.nlm.nih.gov/pubmed/11927606
http://dx.doi.org/10.1083/jcb.200108071
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