Abstract 19019: Loss of Cardiac Myosin Binding Protein-C Leads to Ineffective Contraction and Relaxation Kinetics Which are Reinstated by Reintroducing the Phosphorylated Protein

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Cardiac myosin binding protein-C (cMyBP-C), a heart muscle thick filament protein, can regulate cross-bridge attach/detachment process by its phosphorylation status. Moreover, ablation of cMyBP-C leads to hypertrophy and cardiac dysfunction. Thus, we hypothesize that phosphorylated cMyBP-C provides effective coupling of cross-bridge cycling to [Ca2+]itransients that is lost in cMyBP-C ablation. We test this idea by comparing 3 months old mice models of cMyBP-C knock out (KO), phosphorylation mimetic MyBPC3(t3SD), and WT-control MyBPC3(tWT). KO mice showed worst survival (Kaplan Meier at 18 months: KO: 40.5%; tWT: 91.8%*; t3SD: 95.8%*, Log Rank test p<0.05, *p<0.05 vs KO). By echocardiography, KO hearts exhibited reduced ejection fraction and abbreviated ejection duration (AET/AAT ratio), signifying ineffective contraction. KO also showed myocardium thickening and diastolic dysfunction with elevated E/e’ ratio (e’: tissue Doppler of myocardial relaxation velocity; E: peak blood flow Doppler of mitral blood inflow). We simultaneously measured force and [Ca2+]ion intact papillary muscles pacing at 1-2.5 Hz to elucidate underlying mechanisms. Upon stimulation, [Ca2+]in rises to a peak ahead of force. KO myocardium showed shortest peak Ca to peak force duration (PCa-PF-time or BC segment in graph), signifying inability to sustain contraction. We regressed data to single negative exponential to estimate relaxation and [Ca2+]i decay rate constants of Kforce and KCa respectively. KO muscles show slowest Kforce at 2.5 Hz, meaning impaired relaxation. All models show similar kCa; therefore, depressed relaxation in KO is attributed to cross-bridge cycling but not differences in [Ca2+]in re-uptake. We conclude that cMyBP-C couples cross-bridge cycling kinetics to [Ca2+]intransients; thus, ablation of cMyBP-C depresses myocardium ability to sustain force and impairs relaxation due to ineffective coupling.

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