Myocardial brain-derived neurotrophic factor regulates cardiac bioenergetics through the transcription factor Yin Yang 1.

Abstract

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-1α). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unravelled that BDNF induces PGC-1α 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.

• Authors: Xue Yang, Manling Zhang, Bingxian Xie, Zishan Peng, Janet R Manning, Raymond Zimmerman, Qin Wang, An-Chi Wei, Moustafa Khalifa, Michael Reynolds, Jenny Jin, Matthew Om, Guangshuo Zhu, Djahida Bedja, Hong Jiang, Michael Jurczak, Sruti Shiva, Iain Scott, Brian O'Rourke, David A Kass, Nazareno Paolocci, Ning Feng
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 119 Issue 2 Pg. 571-586 (03 31 2023) ISSN: 1755-3245 [Electronic] England
• PMID: 35704040 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Brain-Derived Neurotrophic Factor
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Transcription Factors
• YY1 Transcription Factor

Topics

• Animals
• Humans
• Mice
• Brain-Derived Neurotrophic Factor (genetics, metabolism)
• Energy Metabolism
• Heart Failure
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• YY1 Transcription Factor (metabolism)