Abstract 17415: Recombinant Human BDNF Can Mimic Effects of Exercise Training in Mice

Abstract

Background: Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, has been known to be increased by exercise training (ET) and associated with exercise capacity, which are dependent on mitochondrial function in the skeletal muscle (SKM). We thus hypothesized that an increase in BDNF and an activation of its binding receptor, tropomyosin-related kinase B (TrkB), could increase the exercise capacity by enhancing mitochondrial function in SKM in mice. Therefore, we investigated whether an administration of recombinant human (rh)BDNF into sedentary (SED) mice could mimic 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 mice was divided into 2 groups of the treatment with vehicle (phosphate-buffered saline; n=10) or rhBDNF (10 mg/kg body weight/day, s.c.; n=10), for 5 weeks. ET was performed by swimming for 90 min/day and 5 times/week. 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 24±1 vs 32±1 J and peak VO2 150±2 vs 166±2 mL/kg/min, p<0.05) and also in SED+rhBDNF to the same extent (work 29±1 and peak VO2 170±2). Serum BDNF levels was significantly increased in SED+rhBDNF compared to SED+vehicle, whereas it did not change in ET+vehicle. BDNF mRNA and protein expressions, and TrkB mRNA were increased in SKM from ET+vehicle compared with SED+vehicle (respectively, p<0.05), whereas they did not change in SED+rhBDNF. Phosphorylation of TrkB, AMP-activated protein kinase (AMPK) and Sirt-1, and PGC-1α protein levels were increased in SED+rhBDNF and ET+vehicle compared with SED+vehicle (respectively, p<0.05). Mitochondrial complex activities and citrate synthase activity were in parallel with these results. In C2C12 myotubes, rhBDNF significantly increased mRNA levels related to mitochondrial function and these effects were completely inhibited by anti-TrkB antibody or AMPK inhibitor, compound C. Conclusions: rhBDNF can mimic the effects of ET on exercise capacity. BDNF-TrkB pathway may play an important role in the beneficial effects of ET on the exercise capacity and SKM function.