Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. Recently, we have investigated whether TrkB Receptors have other functions outside the nervous system. We found that a novel unexpected role of BDNF in regulating the cardiac contraction force independent of the nervous system innervation. This function is mediated by the truncated TrkB.T1 receptor expressed in cardiomyocytes. Loss of TrkB.T1 in these cells impairs calcium signaling and causes cardiomyopathy. TrkB.T1 is activated by BDNF produced by cardiomyocytes suggesting an autocrine/paracrine loop. These findings unveil a novel signaling mechanism in the heart that is activated by BDNF and provide evidence for a global role of this neurotrophin in the homeostasis of the organism by signaling through different TrkB receptor isoforms. Moreover, we are investigating whether activation of TrkB.T1 by BDNF has a protective role during genetic or drug-induced cardiac injury. For example, we have crossed our TrkB.T1 deficient mice with a distrophic mouse model to investigate whether loss of TrkB.T1 worsen the cardiac deficit caused by the mutant dystrophin gene. Moreover, we are testing whether doxorubicin-induced cardiac toxicity is affected by loss of TrkB.T1/BDNF signaling.

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National Cancer Institute (NCI)
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