Journal
CARDIOVASCULAR RESEARCH
Volume 119, Issue 2, Pages 571-586Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvac096
Keywords
BDNF; PGC-1 alpha; YY1 heart failure; cardiac energetics
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BDNF expression is decreased in heart failure patients and increased with exercise. Cardiac-specific knockout of TrkB leads to attenuated cardiac response to exercise and worsened heart failure progression under pathological stress. BDNF induces upregulation of PGC-1 alpha through the Yin Yang 1 signaling pathway, regulating cardiac cellular energetics.
Aims Brain-derived neurotrophic factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, tropomyosin-related kinase receptor (TrkB), are expressed in cardiomyocytes; however, the role of myocardial BDNF signalling in cardiac pathophysiology is poorly understood. Here, we investigated the role of BDNF/TrkB signalling in cardiac stress response to exercise and pathological stress. Methods and results We found that myocardial BDNF expression was increased in mice with swimming exercise but decreased in a mouse heart failure model and human failing hearts. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The downregulation of PGC-1 alpha in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unravelled that BDNF induces PGC-1 alpha upregulation and bioenergetics through a novel signalling pathway, the pleiotropic transcription factor Yin Yang 1. Conclusion Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.
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