Systemic administration of IGF-I enhances oxidative status and reduces contraction-induced injury in skeletal muscles of mdx dystrophic mice.
The absence of dystrophin and resultant disruption of the dystrophin glycoprotein complex renders skeletal muscles of dystrophic patients and dystrophic mdx mice susceptible to contraction-induced injury. Strategies to reduce contraction-induced injury are of critical importance, because this mode of damage contributes to the etiology of myofiber breakdown in the dystrophic pathology. Transgenic overexpression of insulin-like growth factor-I (IGF-I) causes myofiber hypertrophy, increases force production, and can improve the dystrophic pathology in mdx mice. In contrast, the predominant effect of continuous exogenous administration of IGF-I to mdx mice at a low dose (1.0-1.5 mg.kg(-1).day(-1)) is a shift in muscle phenotype from fast glycolytic toward a more oxidative, fatigue-resistant, slow muscle without alterations in myofiber cross-sectional area, muscle mass, or maximum force-producing capacity. We found that exogenous administration of IGF-I to mdx mice increased myofiber succinate dehydrogenase activity, shifted the overall myosin heavy chain isoform composition toward a slower phenotype, and, most importantly, reduced contraction-induced damage in tibialis anterior muscles. The deficit in force-producing capacity after two damaging lengthening contractions was reduced significantly in tibialis anterior muscles of IGF-I-treated (53 +/- 4%) compared with untreated mdx mice (70 +/- 5%, P < 0.05). The results provide further evidence that IGF-I administration can enhance the functional properties of dystrophic skeletal muscle and, compared with results in transgenic mice or virus-mediated overexpression, highlight the disparities in different models of endocrine factor delivery.
Schertzer
Jonathan D
JD
Dept. of Physiology, The University of Melbourne, Victoria 3010, Australia.
Ryall
James G
JG
Lynch
Gordon S
GS
D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000293:injuries / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism
D020033:Protein Isoforms; D007334:Insulin-Like Growth Factor I; D013385:Succinate Dehydrogenase; D018995:Myosin Heavy Chains