Abstract 14510: BDNF-TrkB Pathway Plays an Important Role in the Effects of Exercise Training on Exercise Capacity and Skeletal Muscle Function in Mice

Abstract

Background: Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family that plays a key role in regulating survival, growth, and maintenance of neurons. Plasma BDNF levels have been shown to be increased by exercise training (ET). Moreover, BDNF could directly activate AMP-activated protein kinase (AMPK), which increased fat oxidation, through the phosphorylation of tropomyosin-related kinase B (TrkB) receptor in cultured skeletal muscle (SKM) cells. We thus hypothesized that the activation of BDNF-TrkB signaling could increase the exercise capacity by activating AMPK in SKM in mice. Therefore, we investigated whether this pathway was activated by ET, and the administration of TrkB receptor agonist, 7,8-dihydroxyflavone (DHF), into sedentary (SED) mice could mimiSc the effect of ET on exercise capacity and SKM.

Methods and Results: C57BL/6J mice randomly assigned either SED (n=20) or ET (n=10), SED was further divided into 2 treatment groups with vehicle (17% DMSO in PBS; n=10) or DHF (5 mg/kg body weight, i.p./day; n=10) for 5 weeks. ET was performed by swimming for 90 min/day and 5 times/week. Body and SKM weight did not differ among groups. The work (distance x body weight) and peak oxygen uptake (VO₂) evaluated by treadmill test were significantly increased in ET+vehicle compared to SED+vehicle (work, 33±1 vs 28±1 J and peak VO₂ 170±2 vs 147±2 mL/kg/min, p<0.05) and also in SED+DHF to the same extent (work 36±2 and peak VO₂ 172±2). Plasma BDNF levels did not differ among groups. BDNF mRNA expression and protein as well as TrkB mRNA levels were increased in SKM from ET+vehicle compared with SED+vehicle (p<0.05), whereas they did not change in SED+DHF. Phosphorylation of TrkB, AMPK, and acetyl-CoA carboxylase β expression were increased in ET+vehicle and SED+DHF compared with SED+vehicle (p<0.05). Sirt-1 and PGC-1α mRNA levels were also increased in ET+vehicle and SED+DHF. The administration of DHF into ET mice did not exert such effects on exercise capacity and SKM function.

Conclusions: ET is associated with the activation of BDNF-TrkB signaling and TrkB agonist can mimic its effects on exercise capacity. BDNF-TrkB pathway may play an important role in the beneficial effects of ET on the exercise capacity and SKM function.