Updating the Physiology and Pathophysiology of Cardiac Myosin-Binding Protein-C

LeWinter, Martin M.; Palmer, Bradley M.

doi:10.1161/circheartfailure.115.002146

Cited by 5 publications

(3 citation statements)

References 54 publications

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“…Similarly, a recent study (Rosas et al, 2015 ) demonstrated that impaired ventricular relaxation in 3SA hearts is not due alterations in intracellular Ca 2+ transients, strongly supporting our hypothesis that slowed XB detachment is the predominant factor underlying diastolic dysfunction in 3SA mice (Gresham and Stelzer, 2016 ). Collectively, our data implicates cMyBP-C phosphorylation as a physiological modulator of lusitropy in the heart (Lewinter and Palmer, 2015 ).…”

Section: Discussionsupporting

confidence: 56%

Cardiac Myosin Binding Protein-C Phosphorylation Modulates Myofilament Length-Dependent Activation

et al. 2016

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Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is an important regulator of contractile function, however, its contributions to length-dependent changes in cross-bridge (XB) kinetics is unknown. Therefore, we performed mechanical experiments to quantify contractile function in detergent-skinned ventricular preparations isolated from wild-type (WT) hearts, and hearts expressing non-phosphorylatable cMyBP-C [Ser to Ala substitutions at residues Ser273, Ser282, and Ser302 (i.e., 3SA)], at sarcomere length (SL) 1.9 μm or 2.1μm, prior and following protein kinase A (PKA) treatment. Steady-state force generation measurements revealed a blunting in the length-dependent increase in myofilament Ca2+-sensitivity of force generation (pCa50) following an increase in SL in 3SA skinned myocardium compared to WT skinned myocardium. Dynamic XB behavior was assessed at submaximal Ca2+-activations by imposing an acute rapid stretch of 2% of initial muscle length, and measuring both the magnitudes and rates of resultant phases of force decay due to strain-induced XB detachment and delayed force rise due to recruitment of additional XBs with increased SL (i.e., stretch activation). The magnitude (P2) and rate of XB detachment (krel) following stretch was significantly reduced in 3SA skinned myocardium compared to WT skinned myocardium at short and long SL, and prior to and following PKA treatment. Furthermore, the length-dependent acceleration of krel due to decreased SL that was observed in WT skinned myocardium was abolished in 3SA skinned myocardium. PKA treatment accelerated the rate of XB recruitment (kdf) following stretch at both SL's in WT but not in 3SA skinned myocardium. The amplitude of the enhancement in force generation above initial pre-stretch steady-state levels (P3) was not different between WT and 3SA skinned myocardium at any condition measured. However, the magnitude of the entire delayed force phase which can dip below initial pre-stretch steady-state levels (Pdf) was significantly lower in 3SA skinned myocardium under all conditions, in part due to a reduced magnitude of XB detachment (P2) in 3SA skinned myocardium compared to WT skinned myocardium. These findings demonstrate that cMyBP-C phospho-ablation regulates SL- and PKA-mediated effects on XB kinetics in the myocardium, which would be expected to contribute to the regulation of the Frank-Starling mechanism.

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Section: Discussionsupporting

confidence: 56%

Cardiac Myosin Binding Protein-C Phosphorylation Modulates Myofilament Length-Dependent Activation

et al. 2016

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“…Dephosphorylation of MyBP-C, and reduced Ser 302 phosphorylation ( 37 , 38 ), in particular, has been documented in conditions of chronic human heart failure (HF) ( 37 , 39 ), including patients exhibiting HF with preserved EF (HFpEF) ( 40 ), a detrimental condition caused by a complex interplay of deficits in both diastolic and systolic reserves ( 41 ). Notably, cardiac dysfunction in HFpEF is often not apparent at rest but becomes noticeable during stress or increased workloads, suggesting that an inability to modulate cardiac output leads to exercise intolerance in HFpEF patients ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

Cardiac myosin binding protein-C Ser ³⁰² phosphorylation regulates cardiac β-adrenergic reserve

Mamidi

Gresham

et al. 2017

Sci. Adv.

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“…The myofilaments, which are responsible for the contractile capacity of cardiac tissue, have highly regulated mechanical behavior governed in large part by post-translational modifications and changes in sarcomere stoichiometry (Miyata et al, 2000;Hamdani et al, 2013;LeWinter and Palmer, 2015). The giant protein titin is considered to be a primary determinant of myofilament diastolic tension (Granzier and Irving, 1995) and a significant contributor to myofilament viscoelasticity (Chung et al, 2011).…”

Section: Viscoelasticity and Cardiac Output: Implications For Myocardial Reservementioning

confidence: 99%

Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness

Caporizzo

Prosser

2021

Front. Physiol.

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The heart is viscoelastic, meaning its compliance is inversely proportional to the speed at which it stretches. During diastolic filling, the left ventricle rapidly expands at rates where viscoelastic forces impact ventricular compliance. In heart disease, myocardial viscoelasticity is often increased and can directly impede diastolic filling to reduce cardiac output. Thus, treatments that reduce myocardial viscoelasticity may provide benefit in heart failure, particularly for patients with diastolic heart failure. Yet, many experimental techniques either cannot or do not characterize myocardial viscoelasticity, and our understanding of the molecular regulators of viscoelasticity and its impact on cardiac performance is lacking. Much of this may stem from a reliance on techniques that either do not interrogate viscoelasticity (i.e., use non-physiological rates of strain) or techniques that compromise elements that contribute to viscoelasticity (i.e., skinned or permeabilized muscle preparations that compromise cytoskeletal integrity). Clinically, cardiac viscoelastic characterization is challenging, requiring the addition of strain-rate modulation during invasive hemodynamics. Despite these challenges, data continues to emerge demonstrating a meaningful contribution of viscoelasticity to cardiac physiology and pathology, and thus innovative approaches to characterize viscoelasticity stand to illuminate fundamental properties of myocardial mechanics and facilitate the development of novel therapeutic strategies.

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Updating the Physiology and Pathophysiology of Cardiac Myosin-Binding Protein-C

Cited by 5 publications

References 54 publications

Cardiac Myosin Binding Protein-C Phosphorylation Modulates Myofilament Length-Dependent Activation

Cardiac Myosin Binding Protein-C Phosphorylation Modulates Myofilament Length-Dependent Activation

Cardiac myosin binding protein-C Ser ³⁰² phosphorylation regulates cardiac β-adrenergic reserve

Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness

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Updating the Physiology and Pathophysiology of Cardiac Myosin-Binding Protein-C

Cited by 5 publications

References 54 publications

Cardiac Myosin Binding Protein-C Phosphorylation Modulates Myofilament Length-Dependent Activation

Cardiac Myosin Binding Protein-C Phosphorylation Modulates Myofilament Length-Dependent Activation

Cardiac myosin binding protein-C Ser 302 phosphorylation regulates cardiac β-adrenergic reserve

Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness

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Cardiac myosin binding protein-C Ser ³⁰² phosphorylation regulates cardiac β-adrenergic reserve