Abstract 14146: Brain-derived Neurotrophic Factor Plays an Important Role of Exercise Capacity and Mitochondrial Function in the Skeletal Muscle in Mice With Post-infarct Heart Failure
Background: Exercise intolerance is an independent prognostic factor in patients with heart failure (HF), which is involved in the dysfunction of skeletal muscle. We previously reported that serum brain-derived neurotrophic factor (BDNF) was reduced in HF patients and related to exercise capacity and prognosis. BDNF is known to be produced not only in the brain but also in the skeletal muscle in response to exercise. We thus examined the role of BDNF in the regulation of mitochondrial function in the skeletal muscle from mice with HF.
Methods and Results: Myocardial infarction (MI) was created in male C57BL/6J mice by ligating the left coronary artery, and sham operation was also performed. At two weeks after operation, exercise capacity was significantly decreased in MI compared to sham mice (n=7 for each group). BDNF protein levels examined by western blot analysis were significantly decreased by 62% in the skeletal muscle from MI compared to sham mice (p<0.05). Mitochondrial complex I and II-linked respiration measured by high-resolution respirometry was significantly decreased by 54% in the permeabilized skeletal muscle fiber from MI.
To examine the role of BDNF in the exercise capacity, another set of MI mice were randomly divided into two groups two weeks after operation and subcutaneously treated with recombinant human (rh)BDNF (5 mg/kg BW/day, n=10) or vehicle (n=10) for further two weeks.
The administration of rhBDNF did not affect the cardiac function. Left ventricular end-diastolic diameter and fractional shortening evaluated by echocardiography were similar between MI+vehicle and MI+rhBDNF mice (5.1±0.2 vs. 5.1±0.2 mm, 11.1±1.3 vs. 9.7±1.0 %). The work and the run time were significantly improved in MI+rhBDNF compared to MI+vehicle mice (17.1±1.0 vs.10.3±0.8 J, 1681±46 vs. 1255±47 sec, p<0.05). Mitochondrial complex I and II-linked respiration of electron transport system in the skeletal muscles was significantly improved in MI+rhBDNF compared to MI+vehicle mice (72±7 vs. 43±3 pmol O2/sec/mg fiber, p<0.05).
Conclusions: The administration of rhBDNF can improve the exercise capacity and mitochondrial function in skeletal muscles from mice with HF. The treatment with BDNF may be effective for exercise intolerance in patients with HF.
Author Disclosures: T. Nakajima: None. S. Kinugawa: None. J. Matsumoto: None. S. Takada: None. T. Furihata: None. M. Tsuda: None. T. Katayama: None. H. Nanbu: None. R. Shirakawa: None. S. Maekawa: None. N. Kakutani: None. W. Mizushima: None. T. Yokota: None. K. Okita: None. H. Tsutsui: Research Grant; Significant; Tanabe-Mitsubishi, Daiichi-Sankyo, Takeda, Boehringer-Ingelheim, Bayer, Sanofi. Honoraria; Modest; Boehringer-Ingelheim, Bayer, BMS, Takeda. Honoraria; Significant; Tanabe-Mitsubishi, Daiichi-Sankyo, MSD, Teijin.
- © 2016 by American Heart Association, Inc.