Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling

Shingo Takada, Yoshihiro Masaki, Shintaro Kinugawa, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Masashige Takahashi, Shinichi Harashima, Shouji Matsushima, Takashi Yokota, Shinya Tanaka, Koichi Okita, Hiroyuki Tsutsui

研究成果: ジャーナルへの寄稿記事

33 引用 (Scopus)

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Aims Exercise capacity is reduced in heart failure (HF) patients, due mostly to skeletal muscle abnormalities including impaired energy metabolism, mitochondrial dysfunction, fibre type transition, and atrophy. Glucagon-like peptide-1 (GLP-1) has been shown to improve exercise capacity in HF patients. We investigated the effects of the administration of a dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and skeletal muscle abnormalities in an HF mouse model after myocardial infarction (MI). Methods and results MI was created in male C57BL/6J mice by ligating the left coronary artery, and a sham operation was performed in other mice. The mice were then divided into two groups according to the treatment with or without a DPP-4 inhibitor, MK-0626 [1 mg/kg body weight (BW)/day] provided in the diet. Four weeks later, the exercise capacity evaluated by treadmill test was revealed to be limited in the MI mice, and it was ameliorated in the MI + MK-0626 group without affecting the infarct size or cardiac function. The citrate synthase activity, mitochondrial oxidative phosphorylation capacity, supercomplex formation, and their quantity were reduced in the skeletal muscle from the MI mice, and these decreases were normalized in the MI + MK-0626 group, in association with the improvement of mitochondrial biogenesis. Immunohistochemical staining also revealed that a shift toward the fast-twitch fibre type in the MI mice was also reversed by MK-0626. Favourable effects of MK-0626 were significantly inhibited by treatment of GLP-1 antagonist, Exendin-(9-39) (150 pmol/kg BW/min, subcutaneous osmotic pumps) in MI + MK-0626 mice. Similarly, exercise capacity and mitochondrial function were significantly improved by treatment of GLP-1 agonist, Exendin-4 (1 nmol/kg/BW/h, subcutaneous osmotic pumps). Conclusions A DPP-4 inhibitor may be a novel therapeutic agent against the exercise intolerance seen in HF patients by improving the mitochondrial biogenesis in their skeletal muscle.

元の言語英語
ページ(範囲)338-347
ページ数10
ジャーナルCardiovascular research
111
発行部数4
DOI
出版物ステータス出版済み - 9 1 2016
外部発表Yes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Takada, S., Masaki, Y., Kinugawa, S., Matsumoto, J., Furihata, T., Mizushima, W., Kadoguchi, T., Fukushima, A., Homma, T., Takahashi, M., Harashima, S., Matsushima, S., Yokota, T., Tanaka, S., Okita, K., & Tsutsui, H. (2016). Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling. Cardiovascular research, 111(4), 338-347. https://doi.org/10.1093/cvr/cvw182