Alteration of somatotropic function by proinflammatory cytokines.
Infections direct amino acids away from growth and skeletal muscle accretion toward the hepatic synthesis of acute-phase proteins. The loss of skeletal muscle protein stores results in both a decrease in muscle function and an increase in mortality. In general, muscle protein synthesis is decreased in rodent models of sepsis, as well as after the injection of components of the bacterial cell wall, such as lipopolysaccharide. Although the overexpression of proinflammatory cytokines is known to hasten the loss of skeletal muscle protein, it is not known whether this represents a direct effect of cytokines or results from secondary changes in the IGF system. Plasma concentrations of IGF-I are dramatically lowered by infection in rats, mice, pigs, and steers. The drop in IGF-I often occurs despite an increase in the plasma concentration of somatotropin. Animals are therefore considered to be GH resistant. The IGF bioactivity is determined not only by the plasma concentration of the ligand, but also by IGFBP; IGFBP-3 is the most abundant of these binding proteins and undergoes proteolysis during some catabolic states. In contrast to IGFBP-3, the plasma concentration of inhibitory IGFBP, such as IGFBP-1, is increased during infection. Insulin-like growth factor-binding protein-1 accumulates in skeletal muscle, where it can potentially inhibit IGF-dependent protein synthesis. Insulin-like growth factor-I and IGFBP-1 are regulated at the level of gene transcription by proinflammatory cytokines. Recent studies demonstrate that bacterial components that activate immune cells also activate the innate immune response in skeletal muscle. Lipopolysaccharide increases proinflammatory cytokine messenger RNA expression in muscle from control mice, but not from mice with a mutation in the lipopolysaccharide receptor. Lipopolysaccharide also increases cytokine expression in human and mouse myoblasts. Local expression of cytokines in skeletal muscle may negatively regulate the autocrine synthesis of IGF-I. Current work is focused on deciphering the mechanism by which muscle becomes GH resistant and the development of therapies to maintain muscle protein stores during infection.
Department of Cellular and Molecular Physiology, The Pennsylvania State University, College of Medicine, Hershey 17033, USA. rfrost@psu.edu <rfrost@psu.edu>
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D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000378:metabolism; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D007375:Interleukin-1; D015850:Interleukin-6; D008024:Ligands; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin