ABSTRACT 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. During my K08 award tenure, we found that myocardial BDNF expression was increased in mice with swimming exercise, but decreased in a mouse heart failure model. 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). However, due to the COVID-19 pandemic, the experiments to assess the functional consequence of suppressed PGC-1α and other metabolic transcription factors expression were delayed. In the funded extension period, we will test whether endurance exercise induced cardiac bioenergetic enhancement is attenuated in cTrkB KO mice by mitochondrial biogenesis assessment and mitochondrial respiratory function measurement using Oroboros Respirometer. We also found, in response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The expression of PGC-1α and other metabolic transcription factors were downregulated in cTrkB KO mice exposed to TAC. Consistent with this, mitochondrial DNA copy number and mitochondrial protein abundance was markedly decreased in cTrkB KO mice, resulting in decreased mitochondrial respiratory function. We further unraveled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signaling pathway, the pleiotropic transcription factor Yin Yang 1 (YY1). However, the molecular mechanism of the activation of YY1 by BDNF/TrkB signaling is unclear. In the extension period, we will further delineate the underlying mechanisms of the BDNF induced YY1 activation.