Sex‐based differences in cardiac gene expression and function in BDNF Val66Met mice

Abstract

Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that Val66Met mice exhibit altered cardiac function, and cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p=0.047) and diastolic diameters (14.9%, p=0.022), increased systolic (57.9%, p=0.039) and diastolic volumes (32.7%, p=0.026), and increased stroke volume (25.9%, p=0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, gene expression profile differences between female mutant mice versus littermate controls were greater than that of their male counterparts. In hearts of Val/Met and Met/Met female mice, 121 and 118 genes respectively, were significantly altered compared to littermate controls. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, indicating female-specific susceptibility to altered transcription and downstream functionality.