Cardiac myosin-binding protein-C is a critical mediator of diastolic function
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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.
KeywordsCardiac myosin-binding protein-C MyBPC3 Diastolic dysfunction Heart failure with preserved ejection fraction HFpEF
Heart failure occurs when cardiac output cannot meet the body’s demand. It has an estimated global prevalence of 23 M . Lifetime risks for developing heart failure of a 55-year-old European and a 40-year-old American are 30.2 and 20 %, respectively [2, 15]. Despite treatment advances, 5-year mortality of heart failure patients remains high at 42–80 % . Heart failure can occur with left ventricular ejection fraction (EF) of ≥50 %, which is defined as heart failure with persevered ejection fraction (HFpEF) [29, 49]. Prevalence of HFpEF has increased to 47 % of all heart failure cases . Diastolic dysfunction is the generally accepted cause of HFpEF . Diastolic dysfunction also occurs with heart failure with reduced ejection fraction (HFrEF) , defined as EF < 40 % . Hypertrophic cardiomyopathy (HCM) patients progress to heart failure with type distribution of 48 % HFpEF, 30 % HFrEF, and 22 % outflow obstruction . HCM patients with primarily diastolic dysfunction and without outflow obstruction experience the shortest progression from HCM diagnosis to heart failure . Mere diagnosis of mild diastolic dysfunction carries >eightfold increase in mortality over 5 years . Unfortunately, pathogenic mechanisms that cause diastolic dysfunction remain enigmatic. With this perspective, this review summarizes evidence that cardiac myosin-binding protein-C mediates diastolic function.
Need for cMyBP-C
Cardiac myosin-binding protein-C (cMyBP-C) is a part of the thick filament of the heart muscle . Although cMyBP-C is believed to repress myosin–actin interaction by different mechanisms [12, 18], an important mechanism is that cMyBP-C binding to the rod region of myosin can slow cross-bridge detachment to impair relaxation [1, 12, 26]. Thus, cMyBP-C mutations may lead to diastolic dysfunction. Mutations in cMyBP-C are a leading cause of hypertrophic cardiomyopathy (HCM) . HCM patients, a significant portion of whom carry cMyBP-C mutations, can present with diastolic dysfunction (demonstrated by slowed heart muscle relaxation velocity Ea) before the onset of hypertrophy [19, 33, 34]. A cohort of pediatric HCM patients, 19/27 of whom have cMyBP-C mutations, demonstrates diastolic dysfunction without hypertrophy . Another cohort of patients with three common cMyBP-C mutations found in the Netherlands exhibits hypertrophy with diastolic dysfunction or prehypertrophy with TD evidence of impaired relaxation . The presentation of diastolic dysfunction before the onset of hypertrophy suggests that cMyBP-C mutations cause diastolic dysfunction independent of hypertrophy. Furthermore, a single nucleotide polymorphism in cMyBP-C has been found in diastolic heart failure patients . Thus, clinical evidence suggests that nonmutated/normal cMyBP-C is needed for normal diastolic function.
Mediation of diastolic function by posttranslational modification of cMyBP-C
cMyBP-C phosphorylation levels have been found to be decreased by >50 % in explanted hearts from patients with end-stage heart failure during heart transplant [8, 11, 21, 25]. End-stage failing hearts have severe diastolic and systolic dysfunction along with calcium and metabolic derangements; therefore, it is difficult to assess the impact of cMyBP-C phosphorylation. Samples obtained during myomectomy surgery to relieve outflow obstruction showed that HCM hearts have decreased cMyBP-C phosphorylation levels [8, 10, 21]. HCM hearts exhibit predominantly diastolic dysfunction, implying that reduced cMyBP-C phosphorylation is an underlying cause.
Animal models suggest that cMyBP-C phosphorylation mediates diastolic function. Protein kinase A (PKA) can phosphorylate human cMyBP-C at S275, S284, and S304  and their mouse equivalents (S273, S282, S302) as confirmed by mass spectrometry . Expressing cMyBP-C with S273A, S282A, and S302A and S273D, S282D, and S302D mutations onto cMyBP-C(-/-, Ex3-10) background created cMyBP-C(t3SA) (phosphorylation deficient)  and cMyBP-C(t3SD) (phosphorylation mimetic) [7, 26] mouse models, respectively. These mouse models allow one to elucidate the impact of cMyBP-C phosphorylation at its known PKA sites. Myosin-binding protein C (cMyBP-C)(t3SA) hearts exhibited similar EF [7, 26, 44], reduced Ea (slowed heart muscle relaxation TD velocity, Fig. 2), and increased E/Ea ratio (diastolic dysfunction) [26, 44] in comparison to its wild-type equivalent cMyBP-C(tWT) control, suggesting that reduced cMyBP-C phosphorylation causes predominantly diastolic dysfunction. Furthermore, cMyBP-C(t3SA) mice resemble human HFpEF with shorter voluntary running distances, pulmonary edema, and elevated brain natriuretic peptide levels . Another cMyBP-C phosphorylation-deficient mouse model cMyBP-C(t/t,AllP-) was made by expressing cMyBP-C with five mutations (T272A, S273A, T281A, S282A, S302A) onto the cMyBP-C truncation background of cMyBP-C(t/t) . Unlike cMyBP-C(t3SA), cMyBP-C(t/t, AllP-) hearts showed ~50 % reduction in fractional shortening and severely dilated ventricles in comparison to its cMyBP-C(t/t, WT) control , suggesting that cMyBP-C phosphorylation also mediates systolic function. Differences in mutations and mouse backgrounds probably caused the different phenotypes in these two cMyBP-C phosphorylation-deficient mouse models. Subsequently, expressing combinatorial phosphorylation site mutations (S282A-SAS, S273A/S282D/S302A-ADA, and S273D/S282A/S302D-DAD) onto the cMyBP-C(t/t) background made mutant hearts that exhibit similar EF as their control cMyBP-C(t/t, WT), providing evidence that cMyBP-C phosphorylation has greater impact on diastolic function . More recently, expressing phosphorylation-deficient cMyBP-C mutants of AAD(T272A,S273A,T281A,S282A,S302D) and DAA(T272D,S273D,T281A,S282A,S302A) onto cMyBP-C(t/t) background led to reduced EF and impaired relaxation as evidenced by slowed heart muscle relaxation TD velocity Ea . Conversely, the phosphorylation-mimetic cMyBP-C(t3SD) demonstrated enhanced diastolic function by faster heart muscle relaxation TD velocity Ea (Fig. 2) and reduced E/Ea ratio (enhanced diastolic function) . Together, these findings indicate that cMyBP-C phosphorylation mediates diastolic function.
Posttranslational modifications of cMyBP-C other than phosphorylation may also affect diastolic function. Unilateral nephrectomy and chronic deoxycorticosterone acetate (DOCA) salt treatment will cause diastolic dysfunction . Diastolic dysfunction in this mouse model was attributed to altered myofilament calcium sensitivity due to increased glutathionylation of cMyBP-C . Tetrahydrobiopterin treatment decreased glutathionylation and increased cross-bridge cycling rate to reverse diastolic dysfunction independent of cMyBP-C phosphorylation . Thus, glutathionylation of cMyBP-C may also mediate diastolic dysfunction.
Clinical evidence and animal models demonstrate that cMyBP-C mediates diastolic function. The correlation of intact papillary muscle experiments and in vivo TD measurements suggests that cMyBP-C phosphorylation modulates relative cross-bridge detachment rate with respect to attachment rate to mediate diastolic function. Thus, targeting cMyBP-C phosphorylation holds great potential for the treatment of diastolic dysfunction.
This effort is supported in part by AHA-BGIA7750035, NIH/NHLBI K08HL114877, and Texas A&M University/Baylor Scott & White startup funds to CT.
- 1.Ababou A, Rostkova E, Mistry S, Le Masurier C, Gautel M, Pfuhl M (2008) Myosin binding protein C positioned to play a key role in regulation of muscle contraction: structure and interactions of domain C1. J Mol Biol 384(3):615–630. doi: 10.1016/j.jmb.2008.09.065 PubMedCentralPubMedCrossRefGoogle Scholar
- 2.Bleumink GS, Knetsch AM, Sturkenboom MC, Straus SM, Hofman A, Deckers JW, Witteman JC, Stricker BH (2004) Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. Eur Heart J 25(18):1614–1619. doi: 10.1016/j.ehj.2004.06.038 PubMedCrossRefGoogle Scholar
- 7.Colson BA, Patel JR, Chen PP, Bekyarova T, Abdalla MI, Tong CW, Fitzsimons DP, Irving TC, Moss RL (2012) Myosin binding protein-C phosphorylation is the principal mediator of protein kinase A effects on thick filament structure in myocardium. J Mol Cell Cardiol 53(5):609–616. doi: 10.1016/j.yjmcc.2012.07.012 PubMedCentralPubMedCrossRefGoogle Scholar
- 10.van Dijk SJ, Paalberends ER, Najafi A, Michels M, Sadayappan S, Carrier L, Boontje NM, Kuster DW, van Slegtenhorst M, Dooijes D, dos Remedios C, ten Cate FJ, Stienen GJ, van der Velden J (2012) Contractile dysfunction irrespective of the mutant protein in human hypertrophic cardiomyopathy with normal systolic function. Circ Heart Fail 5(1):36–46. doi: 10.1161/CIRCHEARTFAILURE.111.963702 PubMedCrossRefGoogle Scholar
- 11.El-Armouche A, Pohlmann L, Schlossarek S, Starbatty J, Yeh YH, Nattel S, Dobrev D, Eschenhagen T, Carrier L (2007) Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure. J Mol Cell Cardiol 43(2):223–229. doi: 10.1016/j.yjmcc.2007.05.003 PubMedCrossRefGoogle Scholar
- 13.Fraysse B, Weinberger F, Bardswell SC, Cuello F, Vignier N, Geertz B, Starbatty J, Kramer E, Coirault C, Eschenhagen T, Kentish JC, Avkiran M, Carrier L (2012) Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice. J Mol Cell Cardiol 52(6):1299–1307. doi: 10.1016/j.yjmcc.2012.03.009 PubMedCentralPubMedCrossRefGoogle Scholar
- 19.Ho CY, Carlsen C, Thune JJ, Havndrup O, Bundgaard H, Farrohi F, Rivero J, Cirino AL, Andersen PS, Christiansen M, Maron BJ, Orav EJ, Kober L (2009) Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy. Circ Cardiovasc Genet 2(4):314–321. doi: 10.1161/CIRCGENETICS.109.862128 PubMedCentralPubMedCrossRefGoogle Scholar
- 22.Jeong EM, Monasky MM, Gu L, Taglieri DM, Patel BG, Liu H, Wang Q, Greener I, Dudley SC Jr, Solaro RJ (2013) Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties. J Mol Cell Cardiol 56:44–54. doi: 10.1016/j.yjmcc.2012.12.003 PubMedCentralPubMedCrossRefGoogle Scholar
- 23.Jia W, Shaffer JF, Harris SP, Leary JA (2010) Identification of novel protein kinase A phosphorylation sites in the M-domain of human and murine cardiac myosin binding protein-C using mass spectrometry analysis. J Proteome Res 9(4):1843–1853. doi: 10.1021/pr901006h PubMedCentralPubMedCrossRefGoogle Scholar
- 24.Kasner M, Westermann D, Steendijk P, Gaub R, Wilkenshoff U, Weitmann K, Hoffmann W, Poller W, Schultheiss HP, Pauschinger M, Tschope C (2007) Utility of Doppler echocardiography and tissue Doppler imaging in the estimation of diastolic function in heart failure with normal ejection fraction: a comparative Doppler-conductance catheterization study. Circulation 116(6):637–647. doi: 10.1161/CIRCULATIONAHA.106.661983 PubMedCrossRefGoogle Scholar
- 26.De Lange WJ, Grimes AC, Hegge LF, Spring AM, Brost TM, Ralphe JC (2013) E258K HCM-causing mutation in cardiac MyBP-C reduces contractile force and accelerates twitch kinetics by disrupting the cMyBP-C and myosin S2 interaction. J Gen Physiol 142(3):241–255. doi: 10.1085/jgp.201311018 PubMedCrossRefGoogle Scholar
- 26.Liu Y, Abdalla MI, Alluri H, Souders C, Baudino TA, Powers PA, Patel BG, Warren CM, Solaro JR, Moss RL, Tong CW (2012) Abstract 13462: cardiac myosin binding protein-C phosphorylation is essential for normal diastolic function. Circulation 126(21_MeetingAbstracts):A13462Google Scholar
- 27.Lovelock JD, Monasky MM, Jeong EM, Lardin HA, Liu H, Patel BG, Taglieri DM, Gu L, Kumar P, Pokhrel N, Zeng D, Belardinelli L, Sorescu D, Solaro RJ, Dudley SC Jr (2012) Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity. Circ Res 110(6):841–850. doi: 10.1161/CIRCRESAHA.111.258251 PubMedCentralPubMedCrossRefGoogle Scholar
- 28.Luther PK, Bennett PM, Knupp C, Craig R, Padron R, Harris SP, Patel J, Moss RL (2008) Understanding the organization and role of myosin binding protein C in normal striated muscle by comparison with MyBP-C knockout cardiac muscle. J Mol Biol 384(1):60–72. doi: 10.1016/j.jmb.2008.09.013 PubMedCentralPubMedCrossRefGoogle Scholar
- 29.McMurray JJ et al (2012) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 33(14):1787–1847. doi: 10.1093/eurheartj/ehs104 PubMedCrossRefGoogle Scholar
- 30.Melacini P, Basso C, Angelini A, Calore C, Bobbo F, Tokajuk B, Bellini N, Smaniotto G, Zucchetto M, Iliceto S, Thiene G, Maron BJ (2010) Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J 31(17):2111–2123. doi: 10.1093/eurheartj/ehq136 PubMedCrossRefGoogle Scholar
- 31.Michels M, Soliman OI, Kofflard MJ, Hoedemaekers YM, Dooijes D, Majoor-Krakauer D, ten Cate FJ (2009) Diastolic abnormalities as the first feature of hypertrophic cardiomyopathy in Dutch myosin-binding protein C founder mutations. JACC Cardiovasc Imaging 2(1):58–64. doi: 10.1016/j.jcmg.2008.08.003 PubMedCrossRefGoogle Scholar
- 32.Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A (2009) Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 22(2):107–133. doi: 10.1016/j.echo.2008.11.023 PubMedCrossRefGoogle Scholar
- 33.Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, Quinones MA, Roberts R, Marian AJ (2001) Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation 104(2):128–130PubMedCentralPubMedCrossRefGoogle Scholar
- 34.Nagueh SF, McFalls J, Meyer D, Hill R, Zoghbi WA, Tam JW, Quinones MA, Roberts R, Marian AJ (2003) Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation 108(4):395–398. doi: 10.1161/01.CIR.0000084500.72232.8D PubMedCentralPubMedCrossRefGoogle Scholar
- 37.Poutanen T, Tikanoja T, Jaaskelainen P, Jokinen E, Silvast A, Laakso M, Kuusisto J (2006) Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy-causing mutations in the beta-myosin heavy chain, alpha-tropomyosin, and myosin-binding protein C genes. Am Heart J 151(3):725 e721–725 e729. doi: 10.1016/j.ahj.2005.12.005 CrossRefGoogle Scholar
- 40.Sadayappan S, Gulick J, Osinska H, Barefield D, Cuello F, Avkiran M, Lasko VM, Lorenz JN, Maillet M, Martin JL, Brown JH, Bers DM, Molkentin JD, James J, Robbins J (2011) A critical function for Ser-282 in cardiac Myosin binding protein-C phosphorylation and cardiac function. Circ Res 109(2):141–150. doi: 10.1161/CIRCRESAHA.111.242560 PubMedCentralPubMedCrossRefGoogle Scholar
- 42.Seo JS, Kim DH, Kim WJ, Song JM, Kang DH, Song JK (2010) Peak systolic velocity of mitral annular longitudinal movement measured by pulsed tissue Doppler imaging as an index of global left ventricular contractility. Am J Physiol Heart Circ Physiol 298(5):H1608–1615. doi: 10.1152/ajpheart.01231.2009 PubMedCrossRefGoogle Scholar
- 45.Tong CW, Wu X, Muthuchamy M, Scherman JA, Valdivia HH, Moss RL (2008) Abstract 1578: myosin binding protein C is essential for beta-adrenergic mediated acceleration of cardiac relaxation. Circulation 118(18_MeetingAbstracts):S_350Google Scholar
- 46.Tong CW, Wu X, Sadayappan S, Hudmon A, Muthuchamy M, Ralphe JC, Valdivia HH, Moss RL (2010) Abstract 16507: frequency dependent phosphorylation of cardiac myosin binding protein-C mediates acceleration of myocardial relaxation to support normal diastolic function. Circulation 122(21_MeetingAbstracts):A16507-Google Scholar
- 47.Tong CW, Wu X, Scherman JA, Ralphe JC, Muthuchamy M, Valdivia HH, Moss RL (2009) Abstract 3850: cardiac myosin binding protein C regulates cross-bridge kinetics to affect diastolic function. Circulation 120(18_MeetingAbstracts):S871-bGoogle Scholar
- 48.Wu CK, Huang YT, Lee JK, Chiang LT, Chiang FT, Huang SW, Lin JL, Tseng CD, Chen YH, Tsai CT (2012) Cardiac myosin binding protein C and MAP-kinase activating death domain-containing gene polymorphisms and diastolic heart failure. PLoS One 7(4):e35242. doi: 10.1371/journal.pone.0035242 PubMedCentralPubMedCrossRefGoogle Scholar
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