Disruption of REDD1 gene ameliorates sepsis-induced decrease in mTORC1 signaling but has divergent effects on proteolytic signaling in skeletal muscle.

Abstract

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.

• Authors: Jennifer L Steiner, Kristen T Crowell, Scot R Kimball, Charles H Lang
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 309 Issue 12 Pg. E981-94 (Dec 15 2015) ISSN: 1522-1555 [Electronic] United States
• PMID: 26487002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• Ddit4 protein, mouse
• Multiprotein Complexes
• Transcription Factors
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases

Topics

• Animals
• Down-Regulation
• Female
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, Knockout
• Multiprotein Complexes (metabolism)
• Muscle, Skeletal (metabolism)
• Muscular Atrophy (etiology, metabolism)
• Proteolysis
• Sepsis (complications, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Transcription Factors (genetics, metabolism)