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Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
Refeeding reverses the
muscle protein loss seen with fasting. The physiological regulators and
cellular control sites responsible for this reversal are incompletely
defined. Phosphorylation of phosphorylated heat-acid stabled protein
(PHAS-I) frees eukaryotic initiation factor 4E (eIF4E) and stimulates
protein synthesis by accelerating translation initiation.
Phosphorylation of p70 S6-kinase (p70S6k) is thought to be
involved in the regulation of the synthesis of some ribosomsal proteins
and other selected proteins with polypyrimidine clusters near the
transcription start site. We examined whether phosphorylation of PHAS-I
and p70S6k was increased by feeding and determined the
separate effects of insulin and amino acids on PHAS-I and
p70S6k phosphorylation in rat skeletal muscle in vivo.
Muscle was obtained from rats fed ad libitum or fasted overnight
(n = 5 each). Other fasted rats were infused with insulin (3 µU · min
1 · kg1, euglycemic
clamp), amino acids, or the two combined. Gastrocnemius was
freeze-clamped, and PHAS-I and p70S6k phosphorylation was
measured by quantifying the several phosphorylated forms of these
proteins seen on Western blots. We observed that feeding increased
phosphorylation of both PHAS-I and p70S6k (P < 0.05). Infusion of amino acids alone reproduced the effect of feeding.
Physiological hyperinsulinemia increased p70S6K (P
< 0.05) but not PHAS-I phosphorylation (P = 0.98).
Addition of insulin to amino acid infusion was no more effective than
amino acids alone in promoting PHAS-I and p70S6k
phosphorylation. We conclude that amino acid infusion alone enhances the activation of the protein synthetic pathways in vivo in rat skeletal muscle. This effect is not dependent on increases in plasma
insulin and simulates the activation of protein synthesis that
accompanies normal feeding.
messenger ribonucleic acid translation initiation; protein synthesis; insulin clamp; mammalian target of rapamycin
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