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The effects of acidosis, glutamine starvation and inhibition of the pH sensitive SNAT 2 amino acid transporter on protein metabolism in L6 muscle cells

By Kate Florella Evans

Abstract

Uraemia in end-stage renal disease patients leads to wasting of lean\ud tissue, partly through the effects of acidosis that induce negative protein\ud balance. Insulin resistance in these patients is also a major cause of\ud muscle wasting, suggesting that low pH has a significant effect on insulin\ud signalling in uraemic muscle. The pH sensitive SNAT2 amino acid\ud transporter has been implicated in this because it is strongly inhibited by\ud low pH, and amino acids are a well-established stimulus for the key\ud protein kinase mTOR which regulates protein synthesis. The aims of\ud this study were to determine: (a) the effects of amino acids, (especially\ud L-Gln), and acidosis on insulin signalling and global protein\ud synthesis/proteolysis rates; (b) whether these effects are mimicked by\ud selective inhibition of SNAT2, and (c) whether intracellular amino acid\ud depletion is sufficient to account for the functional effects of SNAT2\ud inhibition.\ud In the L6 skeletal muscle cell-line, inhibition of SNAT2 with the nonmetabolisable\ud SLC38 substrate methylaminoisobutyrate, metabolic\ud acidosis (pH 7.1), or silencing of SNAT2 expression with smallinterfering\ud RNAs, all decreased intracellular amino acid concentrations,\ud mTOR activation, and global protein synthesis; and increased global\ud proteolysis. Acidosis and small-interfering RNA inhibition both decreased\ud phosphatidylinositol-3-kinase and protein kinase B activation, even\ud though this is not regarded as an amino acid sensitive pathway.\ud Extracellular amino acid depletion yielded decreases in intracellular\ud amino acid levels similar to those observed during SNAT2 inhibition, but\ud this failed to mimic the impairment of mTOR signalling observed when\ud SNAT2 was inhibited.\ud It is concluded that, in this muscle model, SNAT2 is able to regulate mTOR activation and protein synthesis rates; and that SNAT2 links acidosis, activity of the phosphatidylinositol-3-kinase/PKB signalling\ud pathway and proteolysis, suggesting that SNAT2 is a key player in the acid-induced insulin resistance which is a prime cause of cachexia in acidotic uraemic patients

Publisher: University of Leicester
Year: 2009
OAI identifier: oai:lra.le.ac.uk:2381/7335

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