Constitutive BDNF/TrkB signaling is required for normal cardiac contraction and relaxation

      During its lifetime, the heart is under the constant influence of the autonomic nervous system, and sympathetic/parasympathetic efferent fiber activation is essential to adjust cardiac performance to increased workload. Yet, the autonomic fibers also contain and release neurotrophins (NTs). However, our grasp of NT influence on myocardial function remains limited and mostly confined to their ability of exerting trophic actions on autonomic efferents and vessels serving the heart. Recently, we reported that brain-derived neurotrophic factor (BDNF), by stimulating sarcolemmal TrkB receptors and triggering intracardiac CaMKII signaling, establishes a tonic control on basal cardiac contractility and relaxation (Feng N et al. PNAS, 2015). Indeed, cardiac-specific TrkB knockout mice (TrkB−/−) display impaired cardiac contraction and relaxation. At cellular level, BDNF enhances normal cardiomyocyte Ca2+ cycling, contractility and relaxation via Ca2+/calmodulin-dependent protein kinase II (CaMKII). Conversely, failing myocytes that harbor increased amount of truncated TrkB (with limited tyrosine kinase activity) and chronically activated CaMKII are almost insensitive to BDNF. Thus, BDNF/TrkB signaling provides a novel pathway by which the peripheral nervous system directly and tonically influences myocardial function, in parallel with β-adrenergic control. Our data provide a mechanistic basis to recent clinical observations showing that lower levels of circulating BDNF correlate with worsening of function in heart failure patients, particularly under exercise conditions. Moreover, they concur to explain why tyrosine kinase inhibitors, used especially to treat certain forms of breast cancer, can directly impair systolic and diastolic function. In essence, alterations in BDNF/TrkB signaling are likely new contributors to acute and chronic cardiac affections.
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