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Cardiac myosin-binding protein-C is a critical mediator of diastolic function.

Tong CW, Nair NA, Doersch KM, Liu Y, Rosas PC - Pflugers Arch. (2014)

Bottom Line: Owing partly to inadequate understanding, HFpEF does not have any effective treatments.Experimental results of both cMyBP-C deletion and reduced cMyBP-C phosphorylation causing diastolic dysfunction suggest that cMyBP-C phosphorylation level modulates cross-bridge detachment rate in relation to ongoing attachment rate to mediate relaxation.Regardless of the exact molecular mechanism, ample clinical and experimental data show that cMyBP-C is a critical mediator of diastolic function.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Texas A&M Health Science Center, 702 Southwest H.K. Dodgen Loop, Temple, TX, 76504, USA, CTong@medicine.tamhsc.edu.

ABSTRACT
Diastolic dysfunction prominently contributes to heart failure with preserved ejection fraction (HFpEF). Owing partly to inadequate understanding, HFpEF does not have any effective treatments. Cardiac myosin-binding protein-C (cMyBP-C), a component of the thick filament of heart muscle that can modulate cross-bridge attachment/detachment cycling process by its phosphorylation status, appears to be involved in the diastolic dysfunction associated with HFpEF. In patients, cMyBP-C mutations are associated with diastolic dysfunction even in the absence of hypertrophy. cMyBP-C deletion mouse models recapitulate diastolic dysfunction despite in vitro evidence of uninhibited cross-bridge cycling. Reduced phosphorylation of cMyBP-C is also associated with diastolic dysfunction in patients. Mouse models of reduced cMyBP-C phosphorylation exhibit diastolic dysfunction while cMyBP-C phosphorylation mimetic mouse models show enhanced diastolic function. Thus, cMyBP-C phosphorylation mediates diastolic function. Experimental results of both cMyBP-C deletion and reduced cMyBP-C phosphorylation causing diastolic dysfunction suggest that cMyBP-C phosphorylation level modulates cross-bridge detachment rate in relation to ongoing attachment rate to mediate relaxation. Consequently, alteration in cMyBP-C regulation of cross-bridge detachment is a key mechanism that causes diastolic dysfunction. Regardless of the exact molecular mechanism, ample clinical and experimental data show that cMyBP-C is a critical mediator of diastolic function. Furthermore, targeting cMyBP-C phosphorylation holds potential as a future treatment for diastolic dysfunction.

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Papillary muscle experiment examples. Top panels show time course of dF/dt normalized to (dF/dt)max. Bottom panels show corresponding time course of normalized intracellular calcium concentrations. dFR = (+dF/dt)max/(−dF/dt)min. Increasing magnitude of dFR represents acceleration of relaxation. a wild type, b cMyBP-C(-/-, Ex3-10), c cMyBP-C(tWT), d cMyBP-C(t3SA), and e cMyBP-C(t3SD). cMyBP-C(-/-, Ex3-10) and cMyBP-C(t3SA) muscles exhibit smaller dFRs that do not change with increasing pacing frequency
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Fig3: Papillary muscle experiment examples. Top panels show time course of dF/dt normalized to (dF/dt)max. Bottom panels show corresponding time course of normalized intracellular calcium concentrations. dFR = (+dF/dt)max/(−dF/dt)min. Increasing magnitude of dFR represents acceleration of relaxation. a wild type, b cMyBP-C(-/-, Ex3-10), c cMyBP-C(tWT), d cMyBP-C(t3SA), and e cMyBP-C(t3SD). cMyBP-C(-/-, Ex3-10) and cMyBP-C(t3SA) muscles exhibit smaller dFRs that do not change with increasing pacing frequency

Mentions: cMyBP-C phosphorylation may mediate diastolic function by modulating the relative cross-bridge detachment rate with respect to cross-bridge attachment rate (Fig. 4). Myocardial stretch activation experiments [43, 44] and motility assays using native thick filament [38] demonstrate that both cMyBP-C phosphorylation and cMyBP-C deletion increase cross-bridge cycling rates. Surprisingly, cMyBP-C deletion causes diastolic dysfunction despite its constitutively fast cross-bridge cycling rates [16, 38, 44]. Correlating echocardiographic TD measurements (Ea, Sa) and intact papillary muscle results solves this paradox. cMyBP-C(-/-, Ex3-10) and cMyBP-C phosphorylation-deficient cMyBP-C(t3SA) hearts show characteristic slowed Ea and reduced Ea/Sa ratio (Fig. 2) [46, 47]. Ea and Sa correspond to (dP/dt)min and (dP/dt)max, respectively [35, 42]. Since pressure is a function of force, then (dF/dt)min, (dF/dt)max, and derivative force ratio (dFR) = (dF/dt)min/(dF/dt)max measured from intact papillary muscles are analogous to Ea, Sa, and Ea/Sa, respectively. cMyBP-C(-/-, Ex3-10) and cMyBP-C(t3SA) papillary muscles show decreased dFR, reflecting reduced Ea/Sa [45, 46]. Increasing dFR equates to acceleration of relaxation because peak relaxation rate (dF/dt)min increases exceed increases in peak force generation rate (dF/dt)max. Increased pacing frequency increases dFR only in papillary muscles with phosphorylatable cMyBP-C (Fig. 3) [45–47]. Increased pacing frequency causes similar shortening of [Ca2+]i decay times in all the mouse models (Fig. 3) [45–47]. Therefore, the accelerated relaxation can be attributed to phosphorylated cMyBP-C increasing cross-bridge detachment rate faster than attachment rate but not to changes in calcium handling. cMyBP-C(-/-, Ex3-10) lacks cMyBP-C to modulate cross-bridge detachment causing an inability to accelerate relaxation (slow and unchanging dFR in Fig. 3) despite its fast cross-bridge cycling, resulting in smaller Ea/Sa (Fig. 2). Similarly, cMyBP-C(t3SA) mutants are unable to increase relative cross-bridge detachment rate, causing depressed dFR (Figs. 3 and 4) and seen at the whole heart level by smaller Ea/Sa (Fig. 2). Furthermore, phosphorylated cMyBP-C has been shown to increase cross-bridge detachment rate without affecting attachment rate [9]. Together, these results combine to suggest that phosphorylated cMyBP-C modulates cross-bridge detachment rate in relation to attachment rate to mediate diastolic function.Fig. 3


Cardiac myosin-binding protein-C is a critical mediator of diastolic function.

Tong CW, Nair NA, Doersch KM, Liu Y, Rosas PC - Pflugers Arch. (2014)

Papillary muscle experiment examples. Top panels show time course of dF/dt normalized to (dF/dt)max. Bottom panels show corresponding time course of normalized intracellular calcium concentrations. dFR = (+dF/dt)max/(−dF/dt)min. Increasing magnitude of dFR represents acceleration of relaxation. a wild type, b cMyBP-C(-/-, Ex3-10), c cMyBP-C(tWT), d cMyBP-C(t3SA), and e cMyBP-C(t3SD). cMyBP-C(-/-, Ex3-10) and cMyBP-C(t3SA) muscles exhibit smaller dFRs that do not change with increasing pacing frequency
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Related In: Results  -  Collection

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Fig3: Papillary muscle experiment examples. Top panels show time course of dF/dt normalized to (dF/dt)max. Bottom panels show corresponding time course of normalized intracellular calcium concentrations. dFR = (+dF/dt)max/(−dF/dt)min. Increasing magnitude of dFR represents acceleration of relaxation. a wild type, b cMyBP-C(-/-, Ex3-10), c cMyBP-C(tWT), d cMyBP-C(t3SA), and e cMyBP-C(t3SD). cMyBP-C(-/-, Ex3-10) and cMyBP-C(t3SA) muscles exhibit smaller dFRs that do not change with increasing pacing frequency
Mentions: cMyBP-C phosphorylation may mediate diastolic function by modulating the relative cross-bridge detachment rate with respect to cross-bridge attachment rate (Fig. 4). Myocardial stretch activation experiments [43, 44] and motility assays using native thick filament [38] demonstrate that both cMyBP-C phosphorylation and cMyBP-C deletion increase cross-bridge cycling rates. Surprisingly, cMyBP-C deletion causes diastolic dysfunction despite its constitutively fast cross-bridge cycling rates [16, 38, 44]. Correlating echocardiographic TD measurements (Ea, Sa) and intact papillary muscle results solves this paradox. cMyBP-C(-/-, Ex3-10) and cMyBP-C phosphorylation-deficient cMyBP-C(t3SA) hearts show characteristic slowed Ea and reduced Ea/Sa ratio (Fig. 2) [46, 47]. Ea and Sa correspond to (dP/dt)min and (dP/dt)max, respectively [35, 42]. Since pressure is a function of force, then (dF/dt)min, (dF/dt)max, and derivative force ratio (dFR) = (dF/dt)min/(dF/dt)max measured from intact papillary muscles are analogous to Ea, Sa, and Ea/Sa, respectively. cMyBP-C(-/-, Ex3-10) and cMyBP-C(t3SA) papillary muscles show decreased dFR, reflecting reduced Ea/Sa [45, 46]. Increasing dFR equates to acceleration of relaxation because peak relaxation rate (dF/dt)min increases exceed increases in peak force generation rate (dF/dt)max. Increased pacing frequency increases dFR only in papillary muscles with phosphorylatable cMyBP-C (Fig. 3) [45–47]. Increased pacing frequency causes similar shortening of [Ca2+]i decay times in all the mouse models (Fig. 3) [45–47]. Therefore, the accelerated relaxation can be attributed to phosphorylated cMyBP-C increasing cross-bridge detachment rate faster than attachment rate but not to changes in calcium handling. cMyBP-C(-/-, Ex3-10) lacks cMyBP-C to modulate cross-bridge detachment causing an inability to accelerate relaxation (slow and unchanging dFR in Fig. 3) despite its fast cross-bridge cycling, resulting in smaller Ea/Sa (Fig. 2). Similarly, cMyBP-C(t3SA) mutants are unable to increase relative cross-bridge detachment rate, causing depressed dFR (Figs. 3 and 4) and seen at the whole heart level by smaller Ea/Sa (Fig. 2). Furthermore, phosphorylated cMyBP-C has been shown to increase cross-bridge detachment rate without affecting attachment rate [9]. Together, these results combine to suggest that phosphorylated cMyBP-C modulates cross-bridge detachment rate in relation to attachment rate to mediate diastolic function.Fig. 3

Bottom Line: Owing partly to inadequate understanding, HFpEF does not have any effective treatments.Experimental results of both cMyBP-C deletion and reduced cMyBP-C phosphorylation causing diastolic dysfunction suggest that cMyBP-C phosphorylation level modulates cross-bridge detachment rate in relation to ongoing attachment rate to mediate relaxation.Regardless of the exact molecular mechanism, ample clinical and experimental data show that cMyBP-C is a critical mediator of diastolic function.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Texas A&M Health Science Center, 702 Southwest H.K. Dodgen Loop, Temple, TX, 76504, USA, CTong@medicine.tamhsc.edu.

ABSTRACT
Diastolic dysfunction prominently contributes to heart failure with preserved ejection fraction (HFpEF). Owing partly to inadequate understanding, HFpEF does not have any effective treatments. Cardiac myosin-binding protein-C (cMyBP-C), a component of the thick filament of heart muscle that can modulate cross-bridge attachment/detachment cycling process by its phosphorylation status, appears to be involved in the diastolic dysfunction associated with HFpEF. In patients, cMyBP-C mutations are associated with diastolic dysfunction even in the absence of hypertrophy. cMyBP-C deletion mouse models recapitulate diastolic dysfunction despite in vitro evidence of uninhibited cross-bridge cycling. Reduced phosphorylation of cMyBP-C is also associated with diastolic dysfunction in patients. Mouse models of reduced cMyBP-C phosphorylation exhibit diastolic dysfunction while cMyBP-C phosphorylation mimetic mouse models show enhanced diastolic function. Thus, cMyBP-C phosphorylation mediates diastolic function. Experimental results of both cMyBP-C deletion and reduced cMyBP-C phosphorylation causing diastolic dysfunction suggest that cMyBP-C phosphorylation level modulates cross-bridge detachment rate in relation to ongoing attachment rate to mediate relaxation. Consequently, alteration in cMyBP-C regulation of cross-bridge detachment is a key mechanism that causes diastolic dysfunction. Regardless of the exact molecular mechanism, ample clinical and experimental data show that cMyBP-C is a critical mediator of diastolic function. Furthermore, targeting cMyBP-C phosphorylation holds potential as a future treatment for diastolic dysfunction.

Show MeSH
Related in: MedlinePlus