title: Disruption of genes encoding eIF4E binding proteins-1 and -2 does not alter basal or sepsis-induced changes in skeletal muscle protein synthesis in male or female mice.
abstract: Sepsis decreases skeletal muscle protein synthesis in part by impairing mTOR activity and the subsequent phosphorylation of 4E-BP1 and S6K1 thereby controlling translation initiation; however, the relative importance of changes in these two downstream substrates is unknown. The role of 4E-BP1 (and -BP2) in regulating muscle protein synthesis was assessed in wild-type (WT) and 4E-BP1/BP2 double knockout (DKO) male mice under basal conditions and in response to sepsis. At 12 months of age, body weight, lean body mass and energy expenditure did not differ between WT and DKO mice. Moreover, in vivo rates of protein synthesis in gastrocnemius, heart and liver did not differ between DKO and WT mice. Sepsis decreased skeletal muscle protein synthesis and S6K1 phosphorylation in WT and DKO male mice to a similar extent. Sepsis only decreased 4E-BP1 phosphorylation in WT mice as no 4E-BP1/BP2 protein was detected in muscle from DKO mice. Sepsis decreased the binding of eIF4G to eIF4E in WT mice; however, eIF4E•eIF4G binding was not altered in DKO mice under either basal or septic conditions. A comparable sepsis-induced increase in eIF4B phosphorylation was seen in both WT and DKO mice. eEF2 phosphorylation was similarly increased in muscle from WT septic mice and both control and septic DKO mice, compared to WT control values. The sepsis-induced increase in muscle MuRF1 and atrogin-1 (markers of proteolysis) as well as TNFα and IL-6 (inflammatory cytokines) mRNA was greater in DKO than WT mice. The sepsis-induced decrease in myocardial and hepatic protein synthesis did not differ between WT and DKO mice. These data suggest overall basal protein balance and synthesis is maintained in muscle of mice lacking both 4E-BP1/BP2 and that sepsis-induced changes in mTOR signaling may be mediated by a down-stream mechanism independent of 4E-BP1 phosphorylation and eIF4E•eIF4G binding.
authors.affiliation: Department of Cellular and Molecular Physiology, and Surgery, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Steiner
authors.affiliation: Department of Cellular and Molecular Physiology, and Surgery, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Pruznak
authors.affiliation: Department of Cellular and Molecular Physiology, and Surgery, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Gina
authors.initials: G
authors.lastname: Deiter
authors.affiliation: Department of Cellular and Molecular Physiology, and Surgery, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Maithili
authors.initials: M
authors.lastname: Navaratnarajah
authors.affiliation: Department of Cellular and Molecular Physiology, and Surgery, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kutzler
authors.affiliation: Department of Cellular and Molecular Physiology, and Surgery, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Scot R
authors.initials: SR
authors.lastname: Kimball
authors.affiliation: Department of Cellular and Molecular Physiology, and Surgery, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D054736:Elongation Factor 2 Kinase / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000172:deficiency / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics*; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; C491255:Eif4ebp2 protein, mouse; D039642:Eukaryotic Initiation Factors; D015850:Interleukin-6; D009124:Muscle Proteins; D010750:Phosphoproteins; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; C546843:mTOR protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; C517690:Eef2k protein, mouse; D054736:Elongation Factor 2 Kinase