Key result
Cardiac TrkB knockout reduces fractional shortening ~46% after pressure overload in preclinical heart failure.
Why the study?
The role of myocardial BDNF signaling in cardiac pathophysiology and its impact on cardiac bioenergetics is poorly understood.
Does myocardial BDNF signaling regulate cardiac bioenergetics and the cardiac stress response in mice?
Does myocardial BDNF signaling regulate cardiac bioenergetics and the cardiac stress response in mice?
Absolute Event Rate: 23.1% vs 43.1%
p-value: p=<0.001
Myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response through the transcription factor Yin Yang 1.
Cardiac TrkB deletion blunts exercise adaptation in mice; hypothesis-generating for BDNF-TrkB targeting in human heart failure.
Circulating 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 signaling in cardiac pathophysiology is poorly understood. We found that 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). The cTrkB KO mice developed an exacerbated heart failure progression with transaortic constriction. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unraveled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signaling pathway, the pleiotropic transcription factor Yin Yang 1 (YY1). 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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Yang et al. (2021) studied Heart failure. Cardiac-specific TrkB knockout vs. Wild-type or MHC-Cre mice was evaluated on Fractional shortening at 6 weeks post-transaortic constriction (p=<0.001). Cardiac-specific TrkB knockout mice displayed exacerbated heart failure progression with significantly reduced fractional shortening (23.1% vs 43.1% in wild-type) 6 weeks after transaortic constriction.
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