The Val66 and Met66 Alleles-Specific Expression of BDNF in Human Muscle and Their Metabolic Responsivity

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.

The BDNF Val66Met Polymorphism is a Relevant, But not Determinant, Risk Factor in the Etiology of Neuropsychiatric Disorders – Current Advances in Human Studies: A Systematic Review

“…In the first in situ study identifying a difference in the allele-specific expression of the BDNF containing the Val66met polymorphism, a decrease in the expression levels of BDNF was shown in individuals heterogenous for the Val66met polymorphism, which is not detected in circulating blood [24]. This is consistent with the available clinical studies to date that have been unable to demonstrate a relationship between the presence of the Val66met polymorphism and alterations in circulating BDNF concentrations [25][26][27][28].…”

“…There has only been one study to date that has humans [24]. Considering that this study was very Their study showed a lower depolarization induced BDNF release, with no effects on the constitutive secretion system in Met66BDNF transfected neurons.…”

Exploration of the Moderating Effects of Physical Activity and Early Life Stress on the Relation between Brain-Derived Neurotrophic Factor (BDNF) rs6265 Variants and Depressive Symptoms among Adolescents

“…It is important to address that the vast majority of studies investigating the Val66- and Met66-variant differences at the protein level have used animal models or cell cultures [ 93 ]. Results from a human study indicated that metabolic stress downregulates the expression of BDNF but not concentrations of plasma BDNF [ 93 ]. An alteration in the pro-BDNF/BDNF ratio deriving from the rs6265 polymorphism might be important to consider [ 94 ].…”

The Molecular Effects of BDNF Synthesis on Skeletal Muscle: A Mini-Review

“…Similar to rodents, the effect of PE on neurotrophin synthesis in human skeletal muscle has also been studied (Matthews et al, 2009;Walsh et al, 2014;de Assis et al, 2021). Nevertheless, in humans, only the acute PE paradigm has been studied.…”

“…This response can result from a delayed muscle response in gene expression (Louis et al, 2007;Walsh et al, 2014). Other evidence suggests a significant reduction of mRNA Bdnf levels after a graded and maximal exercise test (de Assis et al, 2021). Acute metabolic stress caused by exhaustive PE was the main factor to explain the decay in Bdnf expression (de Assis et al, 2021).…”