Dietary GABA induces endogenous synthesis of a novel imidazole peptide homocarnosine in mouse skeletal muscles

Abstract

Carnosine (β-alanyl-l-histidine) is an imidazole dipeptide present at high concentrations in skeletal muscles, where it plays a beneficial role. However, oral intake of carnosine or β-alanine to increase skeletal muscle carnosine levels has disadvantages such as low efficiency and side effects. Therefore, we proposed homocarnosine (γ-aminobutyryl-l-histidine) as a novel alternative imidazole peptide for skeletal muscle based on its structural similarity to carnosine. To induce endogenous homocarnosine synthesis in skeletal muscles, mice were fed a basal diet mixed with 0, 0.5, 2, or 5% γ-aminobutyric acid (GABA) for 6 weeks. As expected, in the control group (0% GABA), GABA and homocarnosine were present in trace concentrations. Skeletal muscle homocarnosine levels were significantly increased in the 2% and 5% GABA intake groups (tenfold, P < 0.01 and 53-fold, P < 0.01; respectively) relative to those of the control group, whereas 0.5% GABA intake induced no such effect. GABA intake had no effect on the levels of carnosine, anserine, and β-alanine. Vigabatrin (inhibitor of GABA transaminase (GABA-T)) administration to mice receiving 2% GABA intake for 2 weeks led to GABA-T inhibition in the liver. Subsequently, a 43-fold increase in circulating GABA levels and a tendency increase in skeletal muscle homocarnosine levels were observed. Therefore, skeletal muscle homocarnosine synthesis can be induced by supplying its substrate GABA in tissues. As GABA availability is tightly regulated by GABA-T via GABA degradation, inhibitors of GABA or β-alanine degradation could be novel potential interventions for increasing skeletal muscle imidazole dipeptides.

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Acknowledgments

This work was supported by Grant-in-Aid for Early Career Scientists (No. 18K14407 to Thanutchaporn Kumrungsee) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT, Tokyo), a grant from NH Foods Ltd. (Tsukuba, Japan), and the Hiroshima University Grant for Female Scholars’ International Collaborative Research.

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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Takeshi Arima, Kanako Sato, and Takumi Komaru. The first draft of the manuscript was written by Thanutchporn Kumrungsee. Mikako Sato, Yasuyuki Oishi, Ai Egusa, and Noriyuki Yanaka critically read the manuscript and made valuable suggestions for its improvement. All authors read and approved the final manuscript. Thanutchaporn Kumrungsee and Takeshi Arima contributed equally to this work.

Corresponding authors

Correspondence to Thanutchaporn Kumrungsee or Noriyuki Yanaka.

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Conflict of interest

Mikako Sato is a patent holder (agent containing imidazole dipeptide-Publication number: 20180140655) and works for NH food Ltd. Although this study was partially supported by the grant from NH Foods Ltd. and some authors work at the company, the funding organization and those authors have no influence on the submitted work and all authors declare that they have no conflict of interest.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. The experiments were approved by the local ethics committee (Ethical Approval No. C17-19, granted by the Ethics Committee, Hiroshima University).

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Kumrungsee, T., Arima, T., Sato, K. et al. Dietary GABA induces endogenous synthesis of a novel imidazole peptide homocarnosine in mouse skeletal muscles. Amino Acids 52, 743–753 (2020). https://doi.org/10.1007/s00726-020-02848-x

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Keywords

  • Imidazole dipeptide
  • Carnosine
  • Homocarnosine
  • Skeletal muscle
  • GABA
  • β-Alanine