Cardiac BDNF/TrkB Signaling Can Be Induced By Calorie Restriction With Improved Physical Activity In Obese Mice

摘要

Central nervous system mediates cardiac dysfunction. Brain-derived neurotrophic factor (BDNF) gene is expressed not only in neurons but in cardiac muscle, but cardioprotective effect of BDNF is not yet clear. We hypothesized that cardiac signaling of BDNF/tyrosine kinase receptor B (TrkB) could be induced by the restriction of food in obese subjects, and that induced BDNF signaling could be beneficial in cardiac dysfunction. KKAY mice were fed ad libitum as control (KKAY), or 60% of ad libitum levels (CR-KKAY). Mice were sacrificed on day 0, 7, 28, and 84 of caloric restriction. Body weight and liver/body weight ratio in CR-KKAY were significantly lower than in KKAY on day 7, 28 and 84. However, heart/ body weight ratio did not differ between KKAY and CR-KKAY. Cardiac BDNF mRNA level in CR-KKAY was significantly higher than that in KKAY (1.2+0.3 vs. 0.8+0.2, P<0.05). Cardiac expression of TrkB in CR-KKAY was significantly lower than that in KKAY on day 28. Hippocampal expression of BDNF in CR-KKAY was significantly higher compared with KKAY on day 28 and 84. Hippocampal weight / body weight ratio was also significantly elevated in CR-KKAY compared with KKAY on day 28 and 84. Physical activity in CR-KKAY was significantly increased compared with that in KKAY on day 84.Cardiac expression of BDNF was induced by caloric restriction with the increase of physical activity in obese mice. Cardiac BDNF may play a role in recovery from obese related dysfunction of the heart. We demonstrate that induced expression of BDNF/TrkB signaling can improve heart failure in obese mammals with the combination of increased hippocampal expression of BDNF. Introduction Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of neurotrophic factors, has important functions in the peripheral and central nervous system of vertebrates [1]. BDNF was originally isolated from the brain; however, it is also expressed in the non-neural tissues [2]. BDNF is expressed in cardiac muscle and may modulate cardiac function. Caloric restriction (CR) is beneficial for myocardial ischemia through the BDNA signaling pathway [3]. Moreover, CR improves heart failure in obese subjects [4] and is closely associated with the increase of hyppocampal BDNF mRNA [5]. However, the relation between BDNF and heart disease is not yet clear [6]. We hypothesized that cardiac and hyppocampal expression of BDNF could be induced by the restriction of food in obese subjects and that induced BDNF signaling could be beneficial in cardiac dysfunction. METHODS Mice and experimental protocolObese KKAY mice were fed ad libitum as control (KKAY, n=18) or 60% restriction of ad libitum levels (CR-KKAY, n=18). As a normal control,C57BL mice were fed ad libitum (C57BL, n=18). Mice were sacrificed on day 0, 7, 28, and 84 after food restriction. Cages were maintained under a light–dark photoperiod (lights on from 9 AM to 5 PM vs. lights off from 5 PM to 9 AM) provided by fluorescent bulbs installed under the ceiling. Environmental air temperature was maintained at between 24 and 250C. Approval for this experiment was obtained from the animal experiment committee at Kanazawa Medical University.Daily activityVoluntary movement during day and night time was analyzed by ACTOMO-10 animal activity monitors (Moter Activity Measurement System, Shintechno, Fukuoka), which continuously compiles data [7]. In brief, movement is allowed within a rectangular enclosure (30x20 cm2) with a side wall equipped with photosensors at 2-cm intervals, as described previously. Total activity counts in each 10-min segment were automatically recorded for 30 min.Results from monitoring were used to determine whether CR might have affected the voluntary movement during the day and night time.Real-time PCRThe heart and brainwere rapidly isolated on an ice-cold platform, then frozen in liquid nitrogen and stored in a -80OC refrigerator until analysis of the related gene expression described previously [8]. RN