SUMMARY In the heart, augmented Ca2+ fluxing drives contractility and ATP generation through mitochondrial Ca2+ loading. Pathologic mitochondrial Ca2+ overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca2+ uptake is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca2+ uptake, augmented ATP production and MPTP opening upon acute Ca2+ challenge. Mice lacking Mcu in the adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca2+ levels were normal in hearts of Mcu-deleted mice and mitochondria lacking MCU eventually loaded with Ca2+ after stress stimulation. Indeed, Mcu-deleted mice were unable to immediately sprint on a treadmill unless warmed-up for 30 minutes. Hence, MCU is a dedicated regulator of short-term mitochondrial Ca2+ loading underlying a “fight-or-flight” response that acutely matches cardiac workload with ATP production.

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day 1,2 despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biologic effect 3. The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischemic injury 4,5. Here we examined the mechanistic basis for cell therapy in mice after ischemia/ reperfusion (I/R) injury, and while heart function was enhanced, it was not associated with new cardiomyocyte production. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2 + and CX3CR1 + macrophages. Intra-cardiac injection of 2 distinct types of adult stem cells, freeze/thaw-killed cells or a chemical inducer of the innate immune response similarly induced regional CCR2 + and CX3CR1 + macrophage accumulation and provided functional rejuvenation to the I/R-injured heart. This selective macrophage response altered cardiac fibroblast activity, reduced border zone extracellular matrix (ECM) content, and enhanced the mechanical properties of the injured area. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

SUMMARY The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent stem cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients.