Regulation of muscle protein synthesis during sepsis and inflammation.
Prolonged sepsis and exposure to an inflammatory milieu decreases muscle protein synthesis and reduces muscle mass. As a result of its ability to integrate diverse signals, including hormones and nutrients, the mammalian target of rapamycin (mTOR) is a dominant regulator in the translational control of protein synthesis. Under postabsorptive conditions, sepsis decreases mTOR kinase activity in muscle, as evidenced by reduced phosphorylation of both eukaryotic initiation factor (eIF)4E-binding protein (BP)-1 and ribosomal S6 kinase (S6K)1. These sepsis-induced changes, along with the redistribution of eIF4E from the active eIF4E.eIF4G complex to the inactive eIF4E.4E-BP1 complex, are preventable by neutralization of tumor necrosis factor (TNF)-alpha but not by antagonizing glucocorticoid action. Although the ability of mTOR to respond to insulin-like growth factor (IGF)-I is not disrupted by sepsis, the ability of leucine to increase 4E-BP1 and S6K1 phosphorylation is greatly attenuated. This "leucine resistance" results from a cooperative interaction between both TNF-alpha and glucocorticoids. Finally, although septic animals are not IGF-I resistant, the anabolic actions of IGF-I are nonetheless reduced because of the development of growth hormone resistance, which decreases both circulating and muscle IGF-I. Herein, we highlight recent advances in the mTOR signaling network and emphasize their connection to the atrophic response observed in skeletal muscle during sepsis. Although many unanswered questions remain, understanding the cellular basis of the sepsis-induced decrease in translational activity will contribute to the rational development of therapeutic interventions and thereby minimize the debilitating affects of the atrophic response that impairs patient recovery.
Lang
Charles H
CH
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. clang@psu.edu
Frost
Robert A
RA
Vary
Thomas C
TC
D000596:Amino Acids / Q000502:physiology; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008954:Models, Biological; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009747:Nutritional Physiological Phenomena; D010448:Peptide Initiation Factors / Q000502:physiology; D014176:Protein Biosynthesis / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology; D039381:RNA Cap-Binding Proteins / Q000378:metabolism / Q000502:physiology; D038601:Ribosomal Protein S6 / Q000378:metabolism; D018805:Sepsis / Q000235:genetics* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D000596:Amino Acids; D009124:Muscle Proteins; D010448:Peptide Initiation Factors; D039381:RNA Cap-Binding Proteins; D038601:Ribosomal Protein S6; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases