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

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

1. Ning Fenga, 
2. Sabine Hukeb, 
3. Guangshuo Zhua, 
4. Carlo G. Tocchettic, 
5. Sa Shia, 
6. Takeshi Aibad,
7. Nina Kaludercice, 
8. Donald B. Hooverf, 
9. Sarah E. Beckg, 
10. Joseph L. Mankowskig, 
11. Gordon F. Tomasellia,
12. Donald M. Bersh, 
13. David A. Kassa, and 
14. Nazareno Paoloccia,i,1

Author Affiliations

1. Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 9, 2014 (received for review September 17, 2014)

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Significance

BDNF plays a key role in neuron development, survival, and function, with actions occurring through the stimulation of the tropomyosin-related kinase receptor B (TrkB) receptor. Whether BDNF/TrkB signaling has any physiologic role in governing myocardial function is unknown. Here we report that intact BDNF/TrkB signaling is required for the heart to fully contract and relax. These actions occur independently from and in addition to β-adrenergic influence. BDNF-induced enhancement of myocardial performance occurs via direct modulation of Ca2+ cycling in a calmodulin-dependent protein kinase II-dependent manner. Thus, BDNF/TrkB signaling represents a previously unidentified way by which the peripheral nervous system controls cardiac muscle physiology. Our study suggests that loss or alterations in BDNF/TrkB stimulation may contribute to the pathogenesis of myocardial dysfunction in acute or chronic disease conditions.

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 Ca2+ cycling, contractility, and relaxation via Ca2+/calmodulin-dependent 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

Footnotes

• 1To whom correspondence should be addressed. Email: npaoloc1@jhmi.edu.

• Author contributions: N.F. and N.P. designed research; N.F., S.H., G.Z., C.G.T., S.S., T.A., N.K., S.E.B., J.L.M., and N.P. performed research; N.F. and N.P. contributed new reagents/analytic tools; N.F., S.H., G.Z., C.G.T., S.S., T.A., N.K., D.B.H., S.E.B., J.L.M., G.F.T., D.M.B., D.A.K., and N.P. analyzed data; and N.F. and N.P. wrote the paper.
• The authors declare no conflict of interest.
• This article is a PNAS Direct Submission.
• This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1417949112/-/DCSupplemental.