Brain-derived neurotrophic factor, epigenetics in stroke skeletal muscle, and exercise training

OBJECTIVE: (1) To compare paretic (P) vs nonparetic (NP) skeletal muscle brain-derived neurotrophic factor (BDNF) and the effects of resistive training (RT) on systemic and skeletal muscle BDNF mRNA expression in stroke; and (2) to compare the DNA methylation profile for BDNF and BDNFAS (BDNF antisense RNA) between P and NP muscle and the effects of aerobic exercise training (AEX) on DNA methylation in stroke. METHODS: In this longitudinal investigation, participants (50–76 years) with chronic stroke underwent a fasting blood draw, a 12-week (3×/week) RT intervention (n = 16), and repeated bilateral vastus lateralis muscle tissue biopsies (n = 10) with BDNF expression determined by RT-PCR. Five stroke survivors completed 6 months of AEX (3×/week) and had bilateral muscle biopsies. DNA methylation status in gene BDNF and BDNFAS was assessed by Illumina 450k methylation array. RESULTS: P muscle had ∼45% lower BDNF mRNA expression than NP muscle (6.79 ± 1.30 vs 10.52 ± 2.06 arbitrary units [AU], p < 0.05), and P muscle exhibited differential methylation status in the DNA sequences of BDNF (3 CpG [5′-C-phosphate-G-3′] sites, p = 0.016–0.044) and BDNFAS (1 CpG site, p = 0.016) compared to NP. Plasma BDNF and muscle BDNF messenger RNA (mRNA) expression did not significantly change after RT. BDNFAS DNA methylation increased after AEX in P relative to NP muscle (p = 0.017). CONCLUSIONS: This is the first evidence that stroke hemiparesis reduces BDNF skeletal muscle expression, with our findings identifying methylation alterations on the DNA sequence of BDNF and BDNFAS gene. Preliminary results further indicate that AEX increases methylation in BDNFAS gene, which presumably could regulate the expression of BDNF.