Local insulin-like growth factor I prevents sepsis-induced muscle atrophy

Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
Metabolism: clinical and experimental (Impact Factor: 3.89). 05/2009; 58(6):787-97. DOI: 10.1016/j.metabol.2009.01.015
Source: PubMed


The present study tests the hypotheses that local bioavailability of insulin-like growth factor I (IGF-I) is capable of regulating muscle protein balance and that muscle-directed IGF-I can selectively maintain muscle mass during bacterial infection. Initial studies in C57BL/6 mice demonstrated that increasing or decreasing bioavailable IGF-I within muscle by local administration of either Leu(24) Ala(31) IGF-I or IGF binding protein 1, respectively, produced proportional changes in surrogate markers (eg, phosphorylation of 4E-BP1 and S6K1) of protein synthesis. We next examined the ability of a sustained local administration of IGF-I to prevent sepsis-induced muscle atrophy over a 5-day period. At the time of cecal ligation and puncture or sham surgery, mice had a time-release pellet containing IGF-I implanted next to the gastrocnemius and a placebo pellet placed in the contralateral limb. Data indicated that IGF-I released locally only affected the adjacent muscle and was not released into the circulation. Gastrocnemius from septic mice containing the placebo pellet was atrophied and had a reduced IGF-I protein content. In contrast, locally directed IGF-I increased IGF-I protein within adjacent muscle to basal control levels. This change was associated with a proportional increase in muscle weight and protein, as well as increased phosphorylation of 4E-BP1 and the redistribution of eIF4E from the inactive eIF4E4EBP1 complex to the active eIF4EeIF4G complex. Local IGF-I also prevented the sepsis-induced increase in atrogin-1 messenger RNA in the exposed muscle. Finally, local IGF-I prevented the sepsis-induced increase in muscle interleukin-6 messenger RNA. Thus, muscle-directed IGF-I attenuates the sepsis-induced atrophic response apparently by increasing muscle protein synthesis and potentially decreasing proteolysis. Collectively, our data suggest that agents that increase the bioavailability of IGF-I within muscle per se might be effective in ameliorating the sepsis-induced loss of muscle mass without having undesirable effects on metabolic processes in distant organs.

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Available from: Charles Lang, Feb 03, 2014
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    • "Previous studies demonstrated the protein retention effect of insulin was likely to be exerted by reducing the protein catabolism after trauma or surgery, because no correlation between changes in muscle protein synthesis and insulin sensitivity was found [45], [46]. However, administration of IGF-1 effectively attenuates the inhibition of protein synthesis in sepsis or trauma and further ameliorates the loss of muscle mass [47], [48]. Therefore, in addition to the nutrient-dependent mechanism described above, the increased mTOR anabolic signaling in the T-HS/EAA group may be partially due to IGF-1 signaling pathway activation. "
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    Preview · Article · Oct 2013 · PLoS ONE
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    • "One such potent mitogen is IGF-I which functions both as a traditional endocrine hormone, but also by an autocrine/paracrine mechanism [42], [62]. In this regard, exogenously delivered IGF-I ameliorates wasting produced by excess glucocorticoids [63], denervation [64], and sepsis [65], and the local over-expression of a muscle-restricted IGF-I isoform can prevent decrement in muscle loss seen with aging [66] and neuromuscular disease [67]. In contrast, others have reported that the localized over-expression of IGF-I in muscle does not prevent the casting-induced decrease in muscle mass and force generation [16], [68]. "
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    • "It is well known that Gram-negative infection (or the administration of lipopolysaccharides) causes loss of skeletal muscle protein. The decrease in muscle mass results from increases in the rate of proteolysis and decreased rates of protein synthesis [53, 54]. A decrease in mTOR activity may explain, at least in part, the impaired muscle protein synthesis. "
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