Sepsis-induced changes in amino acid transporters and leucine signaling via mTOR in skeletal muscle

Lacee J. Laufenberg, Anne M. Pruznak, Maithili Navaratnarajah, Charles H. Lang

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The present study tested the hypothesis that sepsis-induced leucine (Leu) resistance in skeletal muscle is associated with a down-regulation of amino acid transporters important in regulating Leu flux or an impairment in the formation of the Leu-sensitive mTOR-Ragulator complex. Sepsis in adult male rats decreased basal protein synthesis in gastrocnemius, associated with a reduction in mTOR activation as indicated by decreased 4E-BP1 and S6K1 phosphorylation. The ability of oral Leu to increase protein synthesis and mTOR kinase after 1 h was largely prevented in sepsis. Sepsis increased CAT1, LAT2 and SNAT2 mRNA content two- to fourfold, but only the protein content for CAT1 (20 % decrease) differed significantly. Conversely, sepsis decreased the proton-assisted amino acid transporter (PAT)-2 mRNA by 60 %, but without a coordinate change in PAT2 protein. There was no sepsis or Leu effect on the protein content for RagA-D, LAMTOR-1 and -2, raptor, Rheb or mTOR in muscle. The binding of mTOR, PRAS40 and RagC to raptor did not differ for control and septic muscle in the basal condition; however, the Leu-induced decrease in PRAS40·raptor and increase in RagC·raptor seen in control muscle was absent in sepsis. The intracellular Leu concentration was increased in septic muscle, compared to basal control conditions, and oral Leu further increased the intracellular Leu concentration similarly in both control and septic rats. Hence, while alterations in select amino acid transporters are not associated with development of sepsis-induced Leu resistance, the Leu-stimulated binding of raptor with RagC and the recruitment of mTOR/raptor to the endosome-lysosomal compartment may partially explain the inability of Leu to fully activate mTOR and muscle protein synthesis.

Original languageEnglish (US)
Pages (from-to)2787-2798
Number of pages12
JournalAmino Acids
Volume46
Issue number12
DOIs
StatePublished - Dec 2014

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Amino Acid Transport Systems
Leucine
Muscle
Sepsis
Skeletal Muscle
Raptors
TOR Serine-Threonine Kinases
Muscles
Proteins
Rats
Messenger RNA
Phosphorylation
Muscle Proteins
Endosomes
Protons
Phosphotransferases

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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title = "Sepsis-induced changes in amino acid transporters and leucine signaling via mTOR in skeletal muscle",
abstract = "The present study tested the hypothesis that sepsis-induced leucine (Leu) resistance in skeletal muscle is associated with a down-regulation of amino acid transporters important in regulating Leu flux or an impairment in the formation of the Leu-sensitive mTOR-Ragulator complex. Sepsis in adult male rats decreased basal protein synthesis in gastrocnemius, associated with a reduction in mTOR activation as indicated by decreased 4E-BP1 and S6K1 phosphorylation. The ability of oral Leu to increase protein synthesis and mTOR kinase after 1 h was largely prevented in sepsis. Sepsis increased CAT1, LAT2 and SNAT2 mRNA content two- to fourfold, but only the protein content for CAT1 (20 {\%} decrease) differed significantly. Conversely, sepsis decreased the proton-assisted amino acid transporter (PAT)-2 mRNA by 60 {\%}, but without a coordinate change in PAT2 protein. There was no sepsis or Leu effect on the protein content for RagA-D, LAMTOR-1 and -2, raptor, Rheb or mTOR in muscle. The binding of mTOR, PRAS40 and RagC to raptor did not differ for control and septic muscle in the basal condition; however, the Leu-induced decrease in PRAS40·raptor and increase in RagC·raptor seen in control muscle was absent in sepsis. The intracellular Leu concentration was increased in septic muscle, compared to basal control conditions, and oral Leu further increased the intracellular Leu concentration similarly in both control and septic rats. Hence, while alterations in select amino acid transporters are not associated with development of sepsis-induced Leu resistance, the Leu-stimulated binding of raptor with RagC and the recruitment of mTOR/raptor to the endosome-lysosomal compartment may partially explain the inability of Leu to fully activate mTOR and muscle protein synthesis.",
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Sepsis-induced changes in amino acid transporters and leucine signaling via mTOR in skeletal muscle. / Laufenberg, Lacee J.; Pruznak, Anne M.; Navaratnarajah, Maithili; Lang, Charles H.

In: Amino Acids, Vol. 46, No. 12, 12.2014, p. 2787-2798.

Research output: Contribution to journalArticle

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