Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates energy homeostasis, mitochondrial bioenergetics and mediates exercise-induced neurogenesis in the brain. Both BDNF and its receptor Tropomyosin related kinase receptor B (TrkB) are present in the myocardium. However, the role of BDNF/TrkB signaling in myocardial physiology and the myocardial response to pathological stress is largely unknown. My recent first author publication in PNAS found that constitutive myocardial BDNF/TrkB signaling is required for normal cardiac contraction and relaxation. In new preliminary data, we found exercise induced BDNF expression in the heart, whereas BDNF expression was decreased in myocardium from human heart failure patients and mouse heart failure models. The mice with transgenic myocardial BDNF over-expression showed preserved cardiac function against pressure overload induced by transaortic constriction (TAC). Conversely, cardiac specific TrkB-/- mice (cTrkB-/-) displayed accelerated heart failure progression under pressure overload. Moreover, a small molecule TrkB agonist prevented progression of heart failure in mice, suggesting the BDNF/TrkB pathway could be a novel therapeutic target. Importantly, we found the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1?), a master regulator of mitochondrial biogenesis and mitochondrial respiratory function, was decreased in pressure overload in mice, while over- expression of BDNF restored the impaired PGC1? expression in the stressed hearts. In addition, we also found that the expression of myofibrillar isoform of creatine kinase (CK) was decreased in myocardium after TAC, and recovered in cBDNF-tg mice. CK plays a critical role in energy reservation by ATP regeneration through conversion of creatine phosphate (pCr) and ADP. Thus I will test the hypothesis that BDNF/TrkB activation is critical for exercise physiology and protects against pathological stress by improving cardiac bio-energetics, via PGC1? dependent mitochondrial function enhancement and CK mediated ATP regeneration. This hypothesis will be addressed in three specific aims leveraging our novel transgenic mice models: 1) Determine the importance of myocardial BDNF/TrkB on exercise capacity and exercise induced adaptive response; 2) Test whether myocardial BDNF/TrkB signaling protects against pressure overload by activating PGC1?; 3) Test whether myocardial BDNF/TrkB signaling protects against pressure overload by augmenting creatine kinase mediated ATP regeneration

Public Health Relevance

The impaired biochemical energy production is implicated in the deterioration of heart failure, a leading cause of death in US. This proposal will determine how BDNF, a growth factor, improves energy production in the failing heart, which will potentially provide a novel therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL130604-05
Application #
9739189
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Wang, Wayne C
Project Start
2018-01-15
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Feng, Ning; Anderson, Mark E (2017) CaMKII is a nodal signal for multiple programmed cell death pathways in heart. J Mol Cell Cardiol 103:102-109