Local insulin-like growth factor I prevents sepsis-induced muscle atrophy.
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.
Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
Gerald
G
Nystrom
Anne
A
Pruznak
Danuta
D
Huber
Robert A
RA
Frost
Charles H
CH
Lang
D000818:Animals; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000209:etiology / Q000517:prevention & control*; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects; D018805:Sepsis / Q000150:complications*
D015850:Interleukin-6; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I