SYNTHETIC TORPOR IN THE RAT PROTECTS THE HEART FROM ISCHEMIA-REPERFUSION INJURY

During hibernation, animals enter torpor, a reversible hypometabolic state that is characterized by a reduction in body temperature, heart rate and oxygen consumption. Animals that naturally enter hibernation are highly tolerant of ischemia-reperfusion injury, consequently leading to an interest in utilizing aspects of torpor for translational medical applications, such as in critical illness. It is currently unknown, however, whether a torpor-like state is protective in animals that do not naturally enter torpor. Using viral vector-mediated chemogenetic activation of the medial preoptic area (MPA) within the hypothalamus, we induced synthetic torpor in the rat, a species that does not naturally enter torpor. Chemogenetic activation of CAMKIIα expressing neurons within the MPA using intraperitoneal Clozapine-N-oxide (2 mg/kg) recapitulates three key features of torpor, hypothermia, bradycardia and reduced oxygen consumption. We demonstrate this synthetic torpor state is cardioprotective in an ex vivo ischemia-reperfusion injury model, resulting in a 40% reduction in cardiac infarct size. This torpor-induced cardioprotection of the isolated heart is not dependent on prior hypothermia in vivo. Phosphoproteomic analysis of cardiac tissue 90 minutes post synthetic torpor demonstrates that this cardioprotective effect of synthetic torpor may be mediated by parallel activation of cell survival and stress tolerance pathways, alongside inhibition of cell death pathways. These findings indicate that synthetic torpor states can be induced in species that do not naturally enter torpor and provide evidence of cardioprotection, which could be potentially be translated into human critical care settings.