Local IGF-I Prevents Sepsis-Induced Muscle Atrophy

• Published in: Metabolism, clinical and experimental clinical and experimental, 2009-06, Vol.58 (6), p.787-797
• Main Authors: Nystrom, Gerald, Pruznak, Anne, Huber, Danuta, Frost, Robert A., Lang, Charles H.
• Format: Article
• Language: English
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2009.01.015

The present study tests the hypothesis that local bioavailability of 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 (IGFBP)-1, respectively, produced proportional changes in surrogate markers (e.g., 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 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 eIF4E· 4EBP1 complex to the active eIF4E· eIF4G complex. Local IGF-I also prevented the sepsis-induced increase in atrogin-1 mRNA in the exposed muscle. Finally, local IGF-I prevented the sepsis-induced increase in muscle IL-6 mRNA. 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 agents which 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.