N‐terminal region of cardiac myosin binding protein‐C impairs myofilament function

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Cardiac myosin binding protein‐C (cMyBP‐C) is a thick filament protein that plays a critical role in the regulation of sarcomere structure and contractility. Previously, we demonstrated that the N‐terminal fragment of cMyBP‐C (C0‐C1f), released during ischemia‐reperfusion (I‐R) injury, is cytotoxic and significantly impairs contractile function. However, the mechanisms in which C0‐C1f impairs cardiomyocyte contractile function remain unknown. The hypothesis of this study is that C0‐C1f depresses cardiac myofilament function. The molecular mass of C0‐C1f was analyzed by top‐down mass spectrometry. The observed molecular weights were 30974.72 Da and 31989.20 Da for mouse and human species respectively. Permeabilized left ventricular (LV) muscle strips were incubated with purified C0‐C1f. Myofilament function was characterized by measuring active tension‐[Ca2+] relationships to determine changes in maximum tension development (tmax) and Ca2+ sensitivity. Tension development and ATP consumption were simultaneously measured to determine tension‐cost over a range of [Ca2+]. C0‐C1f significantly reduced myofilament Ca2+ sensitivity and tmax, increased tension‐cost, and increased the rate of tension redevelopment (ktr). These data contribute to the understanding of contractile dysfunction following I‐R injury and provide a novel therapeutic target for the treatment of heart failure.