Molecular Pharmacology, Vol 13, 640-651, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition by Serotonin of Amino Acid Release and Protein Degradation in Skeletal Muscle

¹ Departments of Medicine and Cell Biology, Baylor College of Medicine, Houston, Texas 77030

The effect of serotonin (5-hydroxytryptamine) on muscle amino acid and protein metabolism was investigated in vitro, using the isolated intact epitrochlaris preparation of rat skeletal muscle. Increasing concentrations of serotonin (1 nM-0.1 mM) produced a concentration-dependent decrease in the rate of alanine and glutamine release from muscle; intracellular levels of these amino acids were also decreased slightly by serotonin. Muscle alanine reutilization, as determined by [U-¹⁴C]alanine oxidation to ¹⁴CO₂ and incorporation into protein, was unaffected by serotonin, and maximal rates of muscle protein synthesis, as judged by [³H]leucine incorporation into trichloroacetic acid-precipitable protein, were also unaltered. These effects of serotonin were blocked by cyproheptadine and methysergide, but were unaffected by morphine and tetrodotoxin (0.1 , µg/ml). None of these antagonists exhibited substantial independent effects on muscle alanine and glutamine synthesis and release. Exogenous serotonin resulted in a concentration-dependent increase in steady-state levels of intracellular cyclic 3',5'-AMP in these muscle preparations. Theophylline (1 mM) or isobutylmethylxanthine (0.2 mM) potentiated the effects of submaximal concentrations of serotonin (1 µM) on muscle amino acid release, and amplified the increments in muscle cyclic AMP produced by this concentration of serotonin. Cyproheptadine and methysergide, but not morphine or tetrodotoxin, blocked the serotonin-induced increments in muscle cyclic AMP levels. The effects of serotonin on alanine and glutamine synthesis and release from muscle were reproduced by exogenous dibutyryl cyclic AMP. Serotonin did not reduce the rate of formation of alanine and glutamine from exogenous amino acid precursors such as aspartate, cysteine, leucine, and valine. Skeletal muscle proteins in the epitrochlaris preparations were partially labeled with [guanido-¹⁴C]arginine administered in vivo using pulse-chase methods. On incubation of these preparations in vitro, serotonin decreased the rate of loss of ¹⁴C label from trichloroacetic acid-precipitable protein in the muscles. Correspondingly, serotonin also decreased the appearance of ¹⁴C label in the incubation medium and in the supernatant fraction of the muscles obtained after trichloroacetic acid treatment. These data indicate that serotonin inhibits alanine and glutamine synthesis and release from intact skeletal muscle. This effect is mediated by a specific D-class serotonin receptor and appears to require the intermediary participation of muscle cyclic AMP. The mechanism of serotonin action most probably involves primary inhibition of protein degradation, which thereby results in decreased availability of precursor amino acid substrates for conversion to alanine and glutamine. These results indicate that serotonin, like norepinephrine, has direct effects on skeletal muscle metabolism, and that these effects are independent of its vasoactive properties.

Note:
ACKNOWLEDGMENTS I thank Yael Harari and Jannie Corbin for their invaluable assistance in this research. I am grateful to Drs. Arnold Schwartz and Mark Entman for their careful appraisal of the manuscript.

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