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This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/C161    most recent 00399.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schertzer, J. D. Articles by Lynch, G. S. Search for Related Content PubMed PubMed Citation Articles by Schertzer, J. D. Articles by Lynch, G. S.

MUSCLE CELL BIOLOGY AND CELL MOTILITY

Muscle-specific overexpression of IGF-I improves E-C coupling in skeletal muscle fibers from dystrophic mdx mice

¹Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria, Australia; and ²School of Anatomy and Human Biology, The University of Western Australia, Western Australia, Australia

Submitted 3 September 2007 ; accepted in final form 5 November 2007

Duchenne muscular dystrophy (DMD) is a lethal X-linked disease caused by the absence of functional dystrophin. Abnormal excitation-contraction (E-C) coupling has been reported in dystrophic muscle fibers from mdx mice, and alterations in E-C coupling components may occur as a direct result of dystrophin deficiency. We hypothesized that muscle-specific overexpression of insulin-growth factor-1 (IGF-I) would reduce E-C coupling failure in mdx muscle. Mechanically skinned extensor digitorum longus muscle fibers from mdx mice displayed a faster decline in depolarization-induced force responses (DIFR); however, there were no differences in sarcoplasmic reticulum (SR)-mediated Ca²⁺ resequestration or in the properties of the contractile apparatus when compared with nondystrophic controls. The rate of DIFR decline was restored to control levels in fibers from transgenic mdx mice that overexpressed IGF-I in skeletal muscle (mdx/IGF-I mice). Dystrophic muscles have a lower transcript level of a specific dihydropyridine receptor (DHPR) isoform, and IGF-I-mediated changes in E-C coupling were associated with increased transcript levels of specific DHPR isoforms involved in Ca²⁺ regulation. Importantly, IGF-I overexpression also increased the sensitivity of the contractile apparatus to Ca²⁺. The results demonstrate that IGF-I can ameliorate fundamental aspects of E-C coupling failure in dystrophic muscle fibers and that these effects are important for the improvements in cellular function induced by this growth factor.

growth factor; muscular dystrophy; skinned fiber