Heavy and light roles: myosin in the morphogenesis of the heart

England, Jennifer; Loughna, Siobhan

doi:10.1007/s00018-012-1131-1

Cited by 174 publications

(147 citation statements)

References 163 publications

(223 reference statements)

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“…32 Consistent with the severe congenital heart defects we observed in patients with compound heterozygous missense mutations in MYH6, ablation of both copies of Myh6 in mice led to gross heart defects and in utero lethality between d11 and d12. 33 Isoform switching at birth occurs in rodents, with A B Figure 2.…”

supporting

confidence: 77%

“…32 Although MYH7 is the dominant cardiac myosin heavy chain isoform in humans, MYH6 expression in the heart persists from fetal life into adulthood, where it is actively engaged in force generation and muscle contraction. 32 Indeed, MYH6 has been shown to account for 30% and 7% of adult ventricular myosin heavy chain in humans at the mRNA and protein levels, respectively, and it is downregulated in human heart failure. 34 Mice heterozygous for Myh6 disruption had reduced levels of the transcript and protein, yet survived with no structural heart defects.…”

Section: Downloaded Frommentioning

confidence: 99%

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Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

Theis

Zimmermann

Evans

et al. 2015

Circ Cardiovasc Genet

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Here, we used whole genome sequencing (WGS) in HLH probands and phenotypically characterized family members to overcome existing barriers to HLH gene discovery. ThisBackground-The molecular underpinnings of hypoplastic left heart are poorly understood. Staged surgical palliation has dramatically improved survival, yet eventual failure of the systemic right ventricle necessitates cardiac transplantation in a subset of patients. We sought to identify genetic determinants of hypoplastic left heart with latent right ventricular dysfunction in individuals with a Fontan circulation. Methods and Results-Evaluation of cardiac structure and function by echocardiography in patients with hypoplastic left heart and their first-degree relatives identified 5 individuals with right ventricular ejection fraction ≤40% after Fontan operation. Whole genome sequencing was performed on DNA from 21 family members, filtering for genetic variants with allele frequency <1% predicted to alter protein structure or expression. Secondary family-based filtering for de novo and recessive variants revealed rare inherited missense mutations on both paternal and maternal alleles of MYH6, encoding myosin heavy chain 6, in 2 patients who developed right ventricular dysfunction 3 to 11 years postoperatively. Parents and siblings who were heterozygous carriers had normal echocardiograms. Protein modeling of the 4 highly conserved amino acid substitutions, residing in both head and tail domains, predicted perturbation of protein structure and function. Conclusions-In contrast to dominant MYH6 mutations with variable penetrance identified in other congenital heart defects and dilated cardiomyopathy, this study reveals compound heterozygosity for recessive MYH6 mutations in patients with hypoplastic left heart and reduced systemic right ventricular ejection fraction. These findings implicate a shared molecular basis for the developmental arrest and latent myopathy of left and right ventricles, respectively. (Circ Cardiovasc Genet. 2015;8:564-571.

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supporting

confidence: 77%

Section: Downloaded Frommentioning

confidence: 99%

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

Theis

Zimmermann

Evans

et al. 2015

Circ Cardiovasc Genet

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“…Defining these factors may help in elucidating the corresponding mechanisms in heart that regulate the differentiation of cardiac progenitor cells after myocardial infarction (death of myocardial tissue). Some of the factors that have been reported in promoting cardiogenesis include: 1) BMPs (bone morphogenetic proteins) that are members of transforming growth factor β (TGF β) superfamily [18,19]; 2) GATA transcription factors (1–6) and their co-activators Nkx-2 [20]; and 3) ventricular myosin heavy chain (vMHC) [21]. Binding of TGF β to the membrane receptors initiates signaling via MAP kinase pathway and phosphorylating smad family of transcription factors Nkx2.5 [22] which is helpful in regeneration.…”

Section: Introductionmentioning

confidence: 99%

Cardiac tissue inhibitor of matrix metalloprotease 4 dictates cardiomyocyte contractility and differentiation of embryonic stem cells into cardiomyocytes: Road to therapy

Chaturvedi

Kalani

Familtseva

et al. 2015

International Journal of Cardiology

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Background TIMP4 (Tissue Inhibitors of Matrix Metalloprotease 4), goes down in failing hearts and mice lacking TIMP4 show poor regeneration capacity after myocardial infarction (MI). This study is based on our previous observation that administration of cardiac inhibitor of metalloproteinase (~TIMP4) attenuates oxidative stress and remodeling in failing hearts. Therefore, we hypothesize that TIMP4 helps in cardiac regeneration by augmenting contractility and inducing the differentiation of cardiac progenitor cells into cardiomyocytes. Methods To validate this hypothesis, we transfected mouse cardiomyocytes with TIMP4 and TIMP4-siRNA and performed contractility studies in the TIMP4 transfected cardiomyocytes as compared to siRNA-TIMP4 transfected cardiomyocytes. We evaluated the calcium channel gene serca2a (sarcoplasmic reticulum calcium ATPase2a) and mir122a which tightly regulates serca2a to explain the changes in contractility. We treated mouse embryonic stem cells with cardiac extract and cardiac extract minus TIMP4 (using TIMP4 monoclonal antibody) to examine the effect of TIMP4 on differentiation of cardiac progenitor cells. Results Contractility was augmented in the TIMP4 transfected cardiomyocytes as compared to siRNA-TIMP4 transfected cardiomyocytes. There was elevated expression of serca2a in the TIMP4 transformed myocytes and down regulation of mir122a. The cells treated with cardiac extract containing TIMP4 showed cardiac phenotype in terms of Ckit+, GATA4+ and Nkx2.5 expression. Conclusion This is a novel report suggesting that TIMP4 augments contractility and induces differentiation of progenitor cells into cardiac phenotype. In view of the failure of MMP9 inhibitors for cardiac therapy, TIMP4 provides an alternative approach, being an indigenous molecule and a natural inhibitor of MMP9.

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“…The structural domains within myosin help to define its role in muscle contraction. These include the (i) myosin head domain, which forms two globular heads at the N-terminus and reveals binding sites for actin, ATP and divalent cations, (ii) myosin neck domain, which reveal binding sites where the light chains, ELC and MLC2, fold and bind around myosin to regulate myosin motility through formation of the convertor domain and (iii) myosin rod (tail) domain, which forms a dimerized coiled-coil α-helix at the C-terminus, while revealing binding sites for MyBP-C and titin within the sarcomere as well as serving as the backbone to position myosin to interact with actin (England and Loughana, 2013; Rayment et al, 1993; Warrick and Spudich, 1987). A recent study has highlighted a novel interaction between the cardiac-specific domain (C0 domain) of MyBP-C and MLC2 (Ratti et al, 2011).…”

Section: A Cardiac Thick Filament: Major Players and Emerging Role Fmentioning

confidence: 99%

Getting the skinny on thick filament regulation in cardiac muscle biology and disease

Sheikh

Lyon

Chen

2014

Trends in Cardiovascular Medicine

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Thin (actin) filament accessory proteins are thought to be the regulatory force for muscle contraction in cardiac muscle; however, compelling new evidence suggests that thick (myosin) filament regulatory proteins are emerging as having independent and important roles in regulating cardiac muscle contraction. Key to these new findings is a growing body of evidence that point to an influential and more recently, direct role for ventricular myosin light chain-2 (MLC2v) phosphorylation in regulating cardiac muscle contraction, function and disease. This includes the discovery and characterization of a cardiac-specific myosin light chain kinase capable of phosphorylating MLC2v as well as a myosin phosphatase that dephosphorylates MLC2v in the heart, which provides added mechanistic insights on MLC2v regulation within cardiac muscle. Here we review evidence for an emerging and critical role for MLC2v phosphorylation in regulating cardiac myosin cycling kinetics, function and disease, based on recent studies performed in genetic mouse models and humans. We further provide new perspectives on future avenues for targeting these pathways as therapies in alleviating cardiac disease.

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Heavy and light roles: myosin in the morphogenesis of the heart

Cited by 174 publications

References 163 publications

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

Cardiac tissue inhibitor of matrix metalloprotease 4 dictates cardiomyocyte contractility and differentiation of embryonic stem cells into cardiomyocytes: Road to therapy

Getting the skinny on thick filament regulation in cardiac muscle biology and disease

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