Abstract

Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 (Val66Met), which might be correlated with increased risk of cardiovascular events. We previously showed that BDNF correlates with better cardiac function in Duchenne muscular dystrophy (DMD) patients. However, the effect of the Val66Met polymorphism on cardiac function has not been determined. The goal of the current study was to determine the effects of rs6265 on BDNF biomarker suitability and DMD cardiac functions more generally. We assessed cardiovascular and skeletal muscle function in human DMD patients segregated by polymorphic allele. We also compared echocardiographic, electrophysiologic, and cardiomyocyte contractility in C57/BL-6 wild-type mice with rs6265 polymorphism and in mdx/mTR (mDMD) mouse model of DMD. In human DMD patients, plasma BDNF levels had a positive correlation with left ventricular function, opposite to that seen in rs6265 carriers. There was also a substantial decrease in skeletal muscle function in carriers compared to the Val homozygotes. Surprisingly, the opposite was true when cardiac function of DMD carriers and non-carriers were compared. On the other hand, Val66Met wild-type mice had only subtle functional differences at baseline but significantly decreased cardiomyocyte contractility. Our results indicate that the Val66Met polymorphism alters myocyte contractility, conferring worse skeletal muscle function but better cardiac function in DMD patients. Moreover, these results suggest a mechanism for the relative preservation of cardiac tissues compared to skeletal muscle in DMD patients and underscores the complexity of BDNF signaling in response to mechanical workload.

Highlights

  • Brain-derived neurotrophic growth factor (BDNF) is an essential mediator of neuronal growth, differentiation, and survival and plasticity [1]

  • We confirmed our original findings that circulating BDNF correlates positively with cardiac function in Duchenne muscular dystrophy (DMD) patients who express normal BDNF [13], here we show that DMD patients who are carriers of the rs6265 allele exhibit better cardiac function, when compared to age-matched non-carriers

  • Using a knock-in mouse model (Val66Met mice), which harbors the BDNF G→A substitution, we discovered a role for the Val66Met polymorphism in modulating cardiomyocyte contractility as a possible mechanism contributing to altered heart function in the context of dilated cardiomyopathy

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Summary

Introduction

Brain-derived neurotrophic growth factor (BDNF) is an essential mediator of neuronal growth, differentiation, and survival and plasticity [1]. BDNF is important for development of the cardiac microvasculature, basal cardiac contractility in the postnatal heart, and response to cardiac injury [2]. BDNF is produced as a proprotein (proBDNF), which upon cleavage releases an N-terminal fragment (prodomain) and C terminus that represents mature BDNF (mBDNF) [3]. Processed mBDNF binds to tyrosine kinase receptor B (TrkB), which transduces BDNF’s mitogenic, pro-survival, and cardioprotective benefits. Proteolytic cleavage of proBDNF releases a functional N-terminal prodomain along with BDNF. The BDNF prodomain binds to and regulates trafficking and secretion of mBDNF [3,4]

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