Abstract
Brain-derived neurotrophic factor (BDNF) plays an essential role in nervous system formation and functioning, including metabolism. Present only in humans, the “Val66Met” polymorphism of the BDNF gene (BDNF) is suggested to have a negative influence on the etiology of neurological diseases. However, this polymorphism has only been addressed, at the molecular level, in nonhuman models. Knowledge about Val66- and Met66-variant differences, to date, has been achieved at the protein level using either cell culture or animal models. Thus, the purpose of our study was to analyze the impact of the Val66Met polymorphism on BDNF expression in healthy humans and compare the allele-specific responses to metabolic stress. Muscle biopsies from 13 male recreational athletes (34 ± 9 years, 1.80 ± 0.08 m, 76.4 ± 10.5 kg) were obtained before and immediately following a VO2max test. Allele-specific BDNF mRNA concentrations were quantified by droplet digital PCR (ddPCR) in heterozygous and homozygous subjects. The results indicated that BDNF expression levels were influenced by the genotype according to the presence of the polymorphism. BDNF expression from the Met66-coding alleles, in heterozygotes, was 1.3-fold lower than that from the Val66-coding alleles. Total BDNF mRNA levels in these heterozygotes remained below the whole sample’s mean. A partial dominance was detected for the Val66-coding variant on the Met66-coding’s. BDNF expression levels decreased by an average of 1.8-fold following the VO2max test, independent of the individual’s genotype. The results of this study indicate that metabolic stress downregulates BDNF expression but not plasma BDNF concentrations. No correlation between expression level and plasma BDNF concentrations was found.
Highlights
Brain-derived neurotrophic factor (BDNF) is a neurotrophin, a small secretory dimeric protein that appears in all vertebrates with a highly conserved structure (Rafieva and Gasanov, 2016)
The results of BDNF mRNA/B2M∗103 expression analyses from skeletal muscle samples showed a high homogeneity at rest (1.78 ± 0.53 BDNF/103 B2M mRNA molecules) and even higher homogeneity after the VO2max test conditions (0.98 ± 0.33 BDNF/103 B2M mRNA molecules) (Table 2)
Neither the individual differences nor the changes evoked by the VO2max test exceeded a threefold change in BDNF mRNA levels
Summary
Brain-derived neurotrophic factor (BDNF) is a neurotrophin, a small secretory dimeric protein that appears in all vertebrates with a highly conserved structure (Rafieva and Gasanov, 2016). A single nucleotide polymorphism resulting in a substitution of an adenine (A) base by guanine (G) in the BDNF gene (BDNF) has been identified in ∼20% of the population (Maisonpierre et al, 1991; Shimizu et al, 2004). This polymorphism is named “Val66Met” due to a Valine to Methionine substitution in the 66th amino-acid position of the synthesized protein (BDNF) with respect to the A or G genotype (Rafieva and Gasanov, 2016; Hunt et al, 2018). Considering the pivotal function of BDNF, it has been suggested that the BDNF Val66Met may have a role in the etiology of several neurological diseases (Egan et al, 2003; Notaras and van den Buuse, 2018; Shen et al, 2018) and psychiatric disorders (Kishi et al, 2018)
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