Disruption of REDD1 gene ameliorates sepsis-induced decrease in mTORC1 signaling but has divergent effects on proteolytic signaling in skeletal muscle.
Sepsis-induced skeletal muscle atrophy and weakness are due in part to decreased mTORC1-mediated protein synthesis and increased proteolysis via the autophagy-lysosomal system and ubiquitin-proteasome pathway. The REDD1 (regulated in development and DNA damage-1) protein is increased in sepsis and can negatively regulate mTORC1 activity. However, the contribution of REDD1 to the sepsis-induced change in muscle protein synthesis and degradation has not been determined. Sepsis was produced by cecal ligation and puncture in female REDD1(-/-) or wild-type (WT) mice, and end points were assessed 24 h later in gastrocnemius; time-matched, pair-fed controls of each genotype were included. Sepsis increased REDD1 protein 300% in WT mice, whereas REDD1 was absent in REDD1(-/-) muscle. Sepsis decreased protein synthesis and phosphorylation of downstream targets of mTORC1 (S6K1 Thr(389), rpS6 Ser(240/244), 4E-BP1 Ser(65)) in WT but not REDD1(-/-) mice. However, Akt and PRAS40 phosphorylation was suppressed in both sham and septic muscle from REDD1(-/-) mice despite unaltered PDK1, PP2A, or TSC2 expression. Sepsis increased autophagy as indicated by decreased ULK1 Ser(757) phosphorylation and p62 abundance and increased LC3B-II/I in WT mice, whereas these changes were absent in septic REDD1(-/-) mice. Conversely, REDD1 deletion did not prevent the sepsis-induced decrease in IGF-I mRNA or the concomitant increase in IL-6, TNFα, MuRF1, and atrogin1 mRNA expression. Lastly, 5-day survival in a separate set of septic mice did not differ between WT and REDD1(-/-) mice. These data highlight the central role of REDD1 in regulating both protein synthesis and autophagy in skeletal muscle during sepsis.
Department of Cellular and Molecular Physiology and.
Jennifer L
JL
Steiner
Department of Cellular and Molecular Physiology and Department of Surgery, Pennsylvania State College of Medicine, Hershey, Pennsylvania.
Kristen T
KT
Crowell
Department of Cellular and Molecular Physiology and.
Scot R
SR
Kimball
Department of Cellular and Molecular Physiology and Department of Surgery, Pennsylvania State College of Medicine, Hershey, Pennsylvania clang@psu.edu.
Charles H
CH
Lang
D000818:Animals; D015536:Down-Regulation; D005260:Female; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism*; D059748:Proteolysis; D018805:Sepsis / Q000150:complications / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C469992:Ddit4 protein, mouse; D046912:Multiprotein Complexes; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
autophagy; cecal ligation and puncture; critical illness; mechanistic target of rapamycin complex 1; protein synthesis; proteolysis; rgulated in development and DNA damage-1