Ceramide down-regulates System A amino acid transport and protein synthesis in rat skeletal muscle cells.
Skeletal muscle is a major insulin target tissue and has a prominent role in the control of body amino acid economy, being the principal store of free and protein-bound amino acids and a dominant locus for amino acid metabolism. Interplay between diverse stimuli (e.g., hormonal/nutritional/mechanical) modulates muscle insulin action to serve physiological need through the action of factors such as intramuscular signaling molecules. Ceramide, a product of sphingolipid metabolism and cytokine signaling, has a potent contra-insulin action with respect to the transport and deposition of glucose in skeletal muscle, although ceramide effects on muscle amino acid turnover have not previously been documented. Here, membrane permeant C2-ceramide is shown to attenuate the basal and insulin-stimulated activity of the Na+-dependent System A amino acid transporter in rat muscle cells (L6 myotubes) by depletion of the plasma membrane abundance of SNAT2 (a System A isoform). Concomitant with transporter down-regulation, ceramide diminished both intramyocellular amino acid abundance and the phosphorylation of translation regulators lying downstream of mTOR. The physiological outcome of ceramide signaling in this instance is a marked reduction in cellular protein synthesis, a result that is likely to represent an important component of the processes leading to muscle wasting in catabolic conditions.
Hyde
Russell
R
Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, UK.
Hajduch
Eric
E
Powell
Darren J
DJ
Taylor
Peter M
PM
Hundal
Harinder S
HS
D026924:Amino Acid Transport System A / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D000596:Amino Acids / Q000032:analysis / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D002518:Ceramides / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D000596:Amino Acids; D002518:Ceramides; D009124:Muscle Proteins; C412568:Slc38a2 protein, rat; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D005947:Glucose