Abstract 12182: Brain-Derived Neurotrophic Factor Maintains Exercise Capacity and Mitochondrial Function in the Skeletal Muscle Through Ampk-Pgc1α Signaling
Background: Brain-derived neurotrophic factor (BDNF), a member of neurotrophin family, exists not only in the brain but also in the skeletal muscle. We have demonstrated that its serum levels are decreased in heart failure (HF) and are correlated with exercise capacity, indicating that it may regulate skeletal muscle function. We thus determined its physiological role in exercise capacity and mitochondrial function of skeletal muscle by using the gene deletion both in vivo and in vitro.
Methods and Results: Experiments were performed using male wild type (WT, n=8) and BDNF knockout (KO+/-) mice (n=8, 15 to 17 weeks). Body and organ weights, cardiac function assessed by echocardiography, and metabolic parameters including blood sugar, insulin, and lipid profiles did not differ between groups. Plasma BDNF level (15±1 vs. 22±1 pg/mL) as well as BDNF protein levels and phosphorylation of TrkB (tyrosine kinase receptor), BDNF binding receptor were significantly decreased in the skeletal muscle from BDNF KO+/- compared to WT mice (all p<0.05). Citrate synthase (CS) (17±2 vs. 44±2 mM/min/μg protein, p<0.05) and mitochondrial complex I and III activities were significantly decreased in BDNF KO+/-. Phosphorylation of AMPK and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α) levels were significantly lower in BDNF KO+/- by 20% and 25%, respectively (p<0.05). The work (distance x body weight; 26±1 vs. 16±1 J, p<0.05) and peak oxygen uptake (VO2; 162±4 vs. 136±3 mL/kg/min, p<0.05) evaluated by treadmill test were significantly decreased in BDNF KO+/-. Treatment of BDNF KO+/- mice with a specific activator of AMPK (AICAR, 500 mg/kg/day, i.p. for 5 weeks) significantly improved the reduced work (22±1 J), peak VO2 (159±2 mL/kg/min), and CS activity (34±2 mM/min/μg protein) in the skeletal muscle. To further determine the direct role of BDNF in the regulation of mitochondrial function in vitro, knockdown of BDNF in C2C12 myotube by using siRNA decreased the phosphorylation of AMPK and PGC1α protein level of by 70% and 42%, respectively.
Conclusions: BDNF plays an essential role in the maintenance of exercise capacity and the regulation of mitochondrial function in the skeletal muscle thought the AMPK- PGC1α signaling.
Author Disclosures: S. Takada: None. S. Kinugawa: None. S. Matsushima: None. W. Mizushima: None. A. Fukushima: None. T. Furihata: None. T. Kadoguchi: None. T. Yokota: None. T. Suga: None. K. Okita: None. H. Tsutsui: Research Grant; Significant; MSD, Astellas, Ohtsuka, Shionogi, Daiichi-sankyo, Tanabe-Mitsubishi, Novartis, Pfizer. Honoraria; Significant; Daiichi-Sankyo, Tanabe-Mitsubishi, Pfizer, MSD.
- © 2014 by American Heart Association, Inc.