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1 Division of Pulmonary/Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA
2 Division of Pulmonary/Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
3 Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
4 Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: mario.fournier{at}cshs.org.
The aim of this study was to evaluate whether rhIGF-I could attenuate or prevent diaphragm (DIA) fiber atrophy with corticosteroid (CS) administration to emphysematous (EMP) hamsters. DIA muscle IGF-I responses to CS administration with and without exogenous rhIGF-I administration were evaluated. Three groups were studied: 1) EMP; 2) EMP + triamcinolone (T; 0.4 mg/kg/d, i.m.); and 3) EMP+T+IGF-I (600 µg/d by constant infusion). After 4 weeks, the DIA was analyzed histochemically and biochemically (IGF-I mRNA levels by RT-PCR and endogenous and exogenous IGF-I peptide levels immunochemically). Body weights of EMP-T progressively decreased, while those of EMP and EMP-T-IGF-I remained stable despite similarly reduced food intake in both T groups. DIA weight was reduced with T, but preserved with rhIGF-I infusion. DIA fibers proportions were similar among the groups. The cross-sectional areas of types I, IIa and IIx fibers were reduced (17 to 31%) with T administration but unchanged with rhIGF-I infusion. DIA IGF-I mRNA levels were similar across all groups. By contrast, the endogenous DIA IGF-I levels were reduced (41%) in the EMP-T-IGF-I animals. Total DIA IGF-I levels (endogenous + exogenous) were still significantly reduced. IGF-I immunoreactivity confirmed this reduction in all DIA fibers. We conclude that DIA fiber atrophy with T was completely prevented by exogenous rhIGF-I administration. This effect was likely mediated by the pharmacologic influences of exogenously administered rhIGF-I. We speculate that this results from increased bioavailability of free IGF-I to react with muscle receptors. Reduced endogenous IGF-I levels in the DIA likely reflect a negative feedback influence. These results may have important clinical implications for treatment options to offset the adverse effects of CS on the respiratory muscles in patients with chronic lung disorders.
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