Abstract Wed027: Tip60 Depletion in Adult Cardiomyocytes Promotes Calcium Signaling and Mitochondria Function

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Myocardial infarction (MI) leads to cardiomyocyte (CM) loss and contractile dysfunction. We previously reported that genetic knockout (KO) or pharmacological inhibition of Tip60 ( T at- i nteractive p rotein, 60 kD), an acetyltransferase encoded by the Kat5 gene, reduced scarring and improved functional recovery following MI. Transcriptomic analysis indicates the involvement of Tip60 in CM excitation-contraction-metabolism coupling. Here we investigate the role of Tip60 in CM Ca 2+ homeostasis, contractility, mitochondria function, and metabolic properties. In this study, we isolated CMs from adult mice carrying LoxP sites in the Kat5 gene, enabling its specific KO in CMs via tamoxifen-activated Myh6-merCremer recombinase. The extent and kinetics of Ca 2+ transients were studied with rhod-2 AM and fluo-4 AM, their respective localization in mitochondria and cytosol was achieved by a two-step cold/warm loading protocol. Simultaneous measurements of sarcomere shortening were obtained at increasing rates of electrical pulses in the presence of beta-adrenergic agonist to mimic stress conditions. When CMs were challenged with sympathetic stimulation, Tip60 KO improved cytosolic Ca 2+ handling, maintained mitochondria Ca 2+ uptake and buffering, and promoted contractile reserve. Tip60-dependent changes were also confirmed by Ca 2+ retention capacity and membrane potential assessments in isolated mitochondria energized with different substrates. Because Ca 2+ is a key regulator of oxidative metabolism, we further examined CM oxygen consumption and cytosolic glycolysis. In agreement with the changes observed in mitochondria Ca 2+ signaling, Tip60 KO induced a metabolic transition from fatty acid oxidation to anaerobic glycolysis reflected by repressed maximal respiration and elevated glycolytic capacity. The effects of pharmacological inhibition of Tip60, via small MW drugs, on Ca 2+ handling and contraction, mitochondria function, and metabolic reprogramming are being assessed in human induced pluripotent stem cell (hiPSC)-derived CMs. Collectively, these findings suggest that Tip60 modulates CM biomechanical and metabolic pathways, supporting its potential as a therapeutic target for improving functional recovery following MI.

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