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

Abstract

BDNF and its associated tropomyosin-related kinase receptor B (TrkB) nurture vessels and nerves serving the heart. However, the direct effect of BDNF/TrkB signaling on the myocardium is poorly understood. Here we report that cardiac-specific TrkB knockout mice (TrkB −/− ) display impaired cardiac contraction and relaxation, showing that BDNF/TrkB signaling acts constitutively to sustain in vivo myocardial performance. BDNF enhances normal cardiomyocyte Ca 2+ cycling, contractility, and relaxation via Ca 2+ /calmodulindependent protein kinase II (CaMKII). Conversely, failing myocytes, which have increased truncated TrkB lacking tyrosine kinase activity and chronically activated CaMKII, are insensitive to BDNF. Thus, BDNF/TrkB signaling represents a previously unidentified pathway by which the peripheral nervous system directly and tonically influences myocardial function in parallel with β-adrenergic control. Deficits in this system are likely additional contributors to acute and chronic cardiac dysfunction.BDNF | TrkB receptor | cardiac contractility/relaxation | CaMKII | neurotrophins I n the brain, BDNF has a pleiotropic profile, preserving cell viability and function, preventing neuronal degeneration during stress (1), and acting as an antidepressant (2). BDNF is also expressed in various nonneuronal tissues, including smooth and skeletal muscle cells, where it enhances airway smooth muscle cell contractility (3) and acts as a metabolic enhancer (4), respectively.In the mammalian heart, BDNF is essential for organ development because its genetic deletion leads to the thinning of cardiac chambers, microvascular leakage, and ultimately, early death in mice (5). In adult mammals, BDNF governs autonomic transmission to the heart (6) and exerts prominent angiogenic effects (7). Recent evidence also points to the presence of the BDNF receptor, tropomyosin-related kinase receptor B (TrkB), in the myocardium (8). However, the role of myocardial BDNF/ TrkB signaling in cardiac physiology and myocardial response to pathologic stress, independent from its well-known trophic actions on blood vessels and autonomic efferent neurons (9), is largely unknown.In neurons, BDNF regulates Ca 2+ signaling, and calmodulindependent protein kinase II (CaMKII) is one of the downstream effectors of the BDNF/TrkB signaling pathway. Because CaMKII is one of the important regulators of excitation-contraction coupling, and because BDNF also enhances smooth muscle contraction by augmenting intracellular Ca 2+ signaling, we first determined the effects of BDNF on cardiomyocyte contractility, relaxation, and Ca 2+ dynamics. Then, to establish whether BDNF/ TrkB stimulation is relevant in maintaining basal cardiac function in vivo, we generated cardiac-specific TrkB −/− mice by crossing conditional TrkB −/− mice with MHC promoter-driven Cre mice and subjected these mice and their WT littermates to pressurevolume analysis. We further investigated which signaling pathway mediates the BDNF cardiac effects, and finally, we tested whether modulatio...