Abstract 621: Cardiac Myosin Binding Protein-C Phosphorylation in Ser-273 and Ser-282 is Critical to Maintain Cardiac Function During Aging
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Background/hypothesis: Heart failure (HF) afflicts 6.2M Americans as of 2019 and its prevalence is expected to increase due to a growing aging population. HF progression involves depression in contractility and relaxation, which are strongly controlled by phosphorylation of cardiac myosin binding protein-C (cMyBP-C). We hypothesize that phosphorylated cMyBP-C supports normal heart function during aging. Methods: We aged mouse models of cMyBP-C de-phosphorylation mimetic (t3SA: S273A/S282A/S302A mutations), phosphorylation mimetic (t3SD: S273D/S282D/S302D mutations) and WT equivalent expressed onto cMyBP-C(-/-) background (tWT). Results: Western blotting (N=16, 2-24 months) showed that cMyBP-C phosphorylation decreases with aging at S273 and S282, showing strong Pearson correlations with age (see figure; S273P r= -0.931, p<0.0001; S282P r=-0.868, p<0.00001). Simultaneous force and [Ca 2+ ] i measurements on intact papillary muscles showed that phosphorylation-mimetic t3SD has greatest dFR=(-dF/dt)min/(+dF/dt)max, signifying better lusitropy with similar calcium decay rate constant (k Ca ) as others. Echocardiography at 3, 12, 15, 18 months showed that t3SD has preserved ejection fraction, faster peak myocardial relaxation velocity e and preserved posterior ventricular wall thickness with aging. Moreover, t3SD demonstrated superior 600-days survival than others (t3SD 87.5% n=96; tWT 69.3% n=122; t3SA 53.2% n=97; overall LogRank p=0.0002244). Conclusions: De-phosphorylation of cMyBP-C at S273 and S282 contributes to worsening of cardiac function with aging. Conversely, phosphorylated cMyBP-C mitigates aging-related cardiac dysfunction.
