Neal Epstein | National Institutes of Health (original) (raw)

Papers by Neal Epstein

Research paper thumbnail of Cardiac myosin light chain kinase polypeptide, encoding nucleic acid, and methods of use

Research paper thumbnail of Adult Murine Skeletal Muscle Contains Cells That Can Differentiate into Beating Cardiomyocytes In Vitro

PLoS Biology, 2005

It has long been held as scientific fact that soon after birth, cardiomyocytes cease dividing, th... more It has long been held as scientific fact that soon after birth, cardiomyocytes cease dividing, thus explaining the limited restoration of cardiac function after a heart attack. Recent demonstrations of cardiac myocyte differentiation observed in vitro or after in vivo transplantation of adult stem cells from blood, fat, skeletal muscle, or heart have challenged this view. Analysis of these studies has been complicated by the large disparity in the magnitude of effects seen by different groups and obscured by the recently appreciated process of in vivo stem-cell fusion. We now show a novel population of nonsatellite cells in adult murine skeletal muscle that progress under standard primary cell-culture conditions to autonomously beating cardiomyocytes. Their differentiation into beating cardiomyocytes is characterized here by video microscopy, confocal-detected calcium transients, electron microscopy, immunofluorescent cardiac-specific markers, and single-cell patch recordings of cardiac action potentials. Within 2 d after tail-vein injection of these marked cells into a mouse model of acute infarction, the marked cells are visible in the heart. By 6 d they begin to differentiate without fusing to recipient cardiac cells. Three months later, the tagged cells are visible as striated heart muscle restricted to the region of the cardiac infarct.

Research paper thumbnail of Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy

Journal of Clinical Investigation, 1993

Hypertrophic cardiomyopathy is an important inherited disease. The phenotype has been linked, in ... more Hypertrophic cardiomyopathy is an important inherited disease. The phenotype has been linked, in some kindreds, to the beta-myosin heavy chain (,8-MHC) gene. Missense and silent mutations in the 0-MHC gene were used as markers to demonstrate the expression of mutant and normal cardiac fl-MHC gene message in skeletal muscle of hypertrophic cardiomyopathy patients. Mutant 8-myosin, also shown to be present in skeletal muscle by Western blot analysis, translocated actin filaments slower than normal controls in an in vitro motility assay. Thus, single amino acid changes in 8-myosin result in abnormal actomyosin interactions, confirming the primary role of missense mutations in ,-MHC gene in the etiology of hyper

Research paper thumbnail of Investigation and Clinical Significance of Arrhythmias in Patients with Hypertrophic Cardiomyopathy

Journal of Cardiovascular Electrophysiology, 1991

Research paper thumbnail of A Gradient of Myosin Regulatory Light-chain Phosphorylation across the Ventricular Wall Supports Cardiac Torsion

Cold Spring Harbor Symposia on Quantitative Biology, 2002

Research paper thumbnail of Left Ventricular Form and Function

Research paper thumbnail of Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations

Circulation, 1994

BACKGROUND We have previously described two distinct mutations in the beta-myosin heavy chain gen... more BACKGROUND We have previously described two distinct mutations in the beta-myosin heavy chain gene with markedly different clinical presentations and outcome: The 908Leu-->Val mutation was associated with a low disease penetrance and a benign prognosis. In contrast, the 403Arg-->Gln mutation in a Caucasian kindred was associated with a 100% disease penetrance and high incidence of sudden cardiac death. Recently, another mutation, 606Val-->Met, has been reported to be associated with "near normal survival" and offered as evidence for the benign nature of neutral charge substitutions. METHODS AND RESULTS We report (1) a large kindred (245 family members at risk of inheriting the disease gene) with a 256Gly-->Glu mutation characterized by a similar disease penetrance in adults and in children (56% and 60%, respectively) and a cumulative sudden cardiac death rate of only 2% at 50 years of age, (2) a kindred with the 606Val-->Met mutation with four sudden cardiac...

Research paper thumbnail of The Overall Pattern of Cardiac Contraction Depends on a Spatial Gradient of Myosin Regulatory Light Chain Phosphorylation

Cell, 2001

1984; Beyar and Sideman, 1986). It has been previously observed, but not fully understood, that t... more 1984; Beyar and Sideman, 1986). It has been previously observed, but not fully understood, that the epicardial fibers dominate the endocardial fibers (Buchalter et al., 1990; Maier et al., 1992; Young et al., 1994). That is, despite the counter-helical orientation of the endocar

Research paper thumbnail of Cross-Bridge Populations and the Biphasic Time Course of Muscle Relaxation

Biophysical Journal, 2011

the C-terminal domain, thus causing no activation of ATPase activity. With the addition of 1 mM N... more the C-terminal domain, thus causing no activation of ATPase activity. With the addition of 1 mM NEMS-1 the ATPase activation decreased from~225% at pCa 7.5 to~85% at pCa 6.5. The data suggest that in the absence of Ca 2þ at site II strong-binding myosin crossbridges cause opening of more active sites on the thin filament if the C-domain is occupied by Mg 2þ rather than Ca 2þ. This effect could be relevant to the contraction-relaxation kinetics of cardiac muscle. As Ca 2þ dissociates from site II during the relaxing phase of the cardiac cycle, residual Ca 2þ bound at the C-terminus might facilitate the switching off of the thin filament and the detachment of crossbridges from actin.

Research paper thumbnail of Genetic evidence of dissociation (generational skips) of electrical from morphologic forms of hypertrophic cardiomyopathy

The American Journal of Cardiology, 1990

Research paper thumbnail of When Is a Fly in the Ointment a Solution and not a Problem?

Circulation Research, 2006

Research paper thumbnail of The human genes for GM-CSF and IL-3 are closely linked in tandem on chromosome 5

As demonstrated by long-range mapping of restriction endonuclease recognition sequences and genom... more As demonstrated by long-range mapping of restriction endonuclease recognition sequences and genomic cloning. we found that the human genes encoding interleukin 3 (II 3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) are tandemly arrayed on the long arm of chro-mosome 5. separated by 9 kilobases (kb) of DNA. This close physical linkage of genes with similar structure and biologic function suggests that these cytokines may have evolved T HE CONTINUOUS production of mature blood cells from progenitor cells resident in the bone marrow is a complex process that is regulated in part by many different growth factors and cytokines including the hematopoietic colony-stimulating factors (CSFs),”2 erythropoietin (Epo),3 and the interleukins (IL I through IL 6).1.2 Despite the relatedness in function of the different cytokines, many of

Research paper thumbnail of Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles origi... more Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at:

Research paper thumbnail of Immunoinformatic Analysis of T- and B-Cell Epitopes for SARS-CoV-2 Vaccine Design

Vaccines

Currently, there is limited knowledge about the immunological profiles of Severe Acute Respirator... more Currently, there is limited knowledge about the immunological profiles of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We used computer-based immunoinformatic analysis and the newly resolved 3-dimensional (3D) structures of the SARS-CoV-2 S trimeric protein, together with analyses of the immunogenic profiles of SARS-CoV, to anticipate potential B-cell and T-cell epitopes of the SARS-CoV-2 S protein for vaccine design, particularly for peptide-driven vaccine design and serological diagnosis. Nine conserved linear B-cell epitopes and multiple discontinuous B-cell epitopes composed of 69 residues on the surface of the SARS-CoV-2 trimeric S protein were predicted to be highly antigenic. We found that the SARS-CoV-2 S protein has a different antigenic profile than that of the SARS-CoV S protein due to the variations in their primary and 3D structures. Importantly, SARS-CoV-2 may exploit an immune evasion mechanism through two point mutations in the critical and conserved...

Research paper thumbnail of The human genes for GM-CSF and IL 3 are closely linked in tandem on chromosome 5

Blood, 1988

As demonstrated by long-range mapping of restriction endonuclease recognition sequences and genom... more As demonstrated by long-range mapping of restriction endonuclease recognition sequences and genomic cloning, we found that the human genes encoding interleukin 3 (IL 3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) are tandemly arrayed on the long arm of chromosome 5, separated by 9 kilobases (kb) of DNA. This close physical linkage of genes with similar structure and biologic function suggests that these cytokines may have evolved from a common ancestral gene. This linkage in evolution of two relatively divergent genes further implies that some of the other lymphokine and cytokine genes that appear to share as much or more sequence similarity than do IL 3 and GM-CSF may be distantly related members of a cytokine gene family.

Research paper thumbnail of Common miR-590 Variant rs6971711 Present Only in African Americans Reduces miR-590 Biogenesis

PLOS ONE, 2016

MicroRNAs (miRNAs) are recognized as important regulators of cardiac development, hypertrophy and... more MicroRNAs (miRNAs) are recognized as important regulators of cardiac development, hypertrophy and fibrosis. Recent studies have demonstrated that genetic variations which cause alterations in miRNA:target interactions can lead to disease. We hypothesized that genetic variations in miRNAs that regulate cardiac hypertrophy/fibrosis might be involved in generation of the cardiac phenotype in patients diagnosed with hypertrophic cardiomyopathy (HCM). To investigate this question, we Sanger sequenced 18 miRNA genes previously implicated in myocyte hypertrophy/fibrosis and apoptosis, using genomic DNA isolated from the leukocytes of 199 HCM patients. We identified a single nucleotide polymorphism (rs6971711, C57T SNP) at the 17th position of mature miR-590-3p (= 57th position of pre-miR-590) that is common in individuals of African ancestry. SNP frequency was higher in African American HCM patients (n = 55) than ethnically-matched controls (n = 100), but the difference was not statistically significant (8.2% vs. 6.5%; p = 0.5). Using a cell culture system, we discovered that presence of this SNP resulted in markedly lower levels of mature miR-590-5p (39 ± 16%, p<0.003) and miR-590-3p (20 ± 2%, p<0.003), when compared with wild-type (WT) miR-590, without affecting levels of pri-miR-590 and pre-miR-590. Consistent with this finding, the SNP resulted in reduced target suppression when compared to WT miR-590 (71% suppression by WT vs 60% suppression by SNP, p<0.03). Since miR-590 can regulate TGF-β, Activin A and Akt signaling, SNP-induced reduction in miR-590 biogenesis could influence cardiac phenotype by de-repression of these signaling pathways. Since the SNP is only present in African Americans, population studies in this patient

Research paper thumbnail of The in vitro motility activity of -cardiac myosin depends on the nature of the -myosin heavy chain gene mutation in hypertrophic cardiomyopathy

J Muscle Res Cell Motil, 1997

Research paper thumbnail of Mechanistic role of movement and strain sensitivity in muscle contraction

Proceedings of the National Academy of Sciences of the United States of America, Jan 14, 2009

Tension generation can be studied by applying step perturbations to contracting muscle fibers and... more Tension generation can be studied by applying step perturbations to contracting muscle fibers and subdividing the mechanical response into exponential phases. The de novo tension-generating isomerization is associated with one of these phases. Earlier work has shown that a temperature jump perturbs the equilibrium constant directly to increase tension. Here, we show that a length jump functions quite differently. A step release (relative movement of thick and thin filaments) appears to release a steric constraint on an ensemble of noncompetent postphosphate release actomyosin cross-bridges, enabling them to generate tension, a concentration jump in effect. Structural studies [Taylor KA, et al. (1999) Tomographic 3D reconstruction of quick-frozen, Ca(2+)-activated contracting insect flight muscle. Cell 99:421-431] that map to these kinetics indicate that both catalytic and lever arm domains of noncompetent myosin heads change angle on actin, whereas lever arm movement alone mediates ...

Research paper thumbnail of The molecular biology and pathophysiology of hypertrophic cardiomyopathy due to mutations in the beta myosin heavy chains and the essential and regulatory light chains

Advances in experimental medicine and biology, 1998

Hypertrophic cardiomyopathy (HCM) is perhaps the most common cause of inherited sudden death in o... more Hypertrophic cardiomyopathy (HCM) is perhaps the most common cause of inherited sudden death in otherwise healthy young individuals. There are presently seven known genes in which mutations have been shown to cause the disease. The first identified disease gene was beta myosin heavy chain (BMHC). Our laboratory has identified 32 distinct BMHC gene mutations in 62 kindreds after screening representatives of over 400 kindreds. Virtually all but one of approximately 50 known mutations are restricted to the head or head-rod junction region of the molecule. We have used the mutant alleles of the BMHC gene to demonstrate that both mutant message and protein is present in the skeletal muscle of patients with HCM. Muscle biopsies from patients with identified BMHC mutations show abnormal histology. Isolated myosin and skinned fibers from these patients have abnormal mechanical properties. The BMHC gene mutations are clustered in 4 regions of the myosin head. Because one of these regions is ...

Research paper thumbnail of Mechanistic role of movement and strain sensitivity in muscle contraction

Proceedings of The National Academy of Sciences, 2009

Tension generation can be studied by applying step perturbations to contracting muscle fibers and... more Tension generation can be studied by applying step perturbations to contracting muscle fibers and subdividing the mechanical response into exponential phases. The de novo tension-generating isomerization is associated with one of these phases. Earlier work has shown that a temperature jump perturbs the equilibrium constant directly to increase tension. Here, we show that a length jump functions quite differently. A

Research paper thumbnail of Cardiac myosin light chain kinase polypeptide, encoding nucleic acid, and methods of use

Research paper thumbnail of Adult Murine Skeletal Muscle Contains Cells That Can Differentiate into Beating Cardiomyocytes In Vitro

PLoS Biology, 2005

It has long been held as scientific fact that soon after birth, cardiomyocytes cease dividing, th... more It has long been held as scientific fact that soon after birth, cardiomyocytes cease dividing, thus explaining the limited restoration of cardiac function after a heart attack. Recent demonstrations of cardiac myocyte differentiation observed in vitro or after in vivo transplantation of adult stem cells from blood, fat, skeletal muscle, or heart have challenged this view. Analysis of these studies has been complicated by the large disparity in the magnitude of effects seen by different groups and obscured by the recently appreciated process of in vivo stem-cell fusion. We now show a novel population of nonsatellite cells in adult murine skeletal muscle that progress under standard primary cell-culture conditions to autonomously beating cardiomyocytes. Their differentiation into beating cardiomyocytes is characterized here by video microscopy, confocal-detected calcium transients, electron microscopy, immunofluorescent cardiac-specific markers, and single-cell patch recordings of cardiac action potentials. Within 2 d after tail-vein injection of these marked cells into a mouse model of acute infarction, the marked cells are visible in the heart. By 6 d they begin to differentiate without fusing to recipient cardiac cells. Three months later, the tagged cells are visible as striated heart muscle restricted to the region of the cardiac infarct.

Research paper thumbnail of Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy

Journal of Clinical Investigation, 1993

Hypertrophic cardiomyopathy is an important inherited disease. The phenotype has been linked, in ... more Hypertrophic cardiomyopathy is an important inherited disease. The phenotype has been linked, in some kindreds, to the beta-myosin heavy chain (,8-MHC) gene. Missense and silent mutations in the 0-MHC gene were used as markers to demonstrate the expression of mutant and normal cardiac fl-MHC gene message in skeletal muscle of hypertrophic cardiomyopathy patients. Mutant 8-myosin, also shown to be present in skeletal muscle by Western blot analysis, translocated actin filaments slower than normal controls in an in vitro motility assay. Thus, single amino acid changes in 8-myosin result in abnormal actomyosin interactions, confirming the primary role of missense mutations in ,-MHC gene in the etiology of hyper

Research paper thumbnail of Investigation and Clinical Significance of Arrhythmias in Patients with Hypertrophic Cardiomyopathy

Journal of Cardiovascular Electrophysiology, 1991

Research paper thumbnail of A Gradient of Myosin Regulatory Light-chain Phosphorylation across the Ventricular Wall Supports Cardiac Torsion

Cold Spring Harbor Symposia on Quantitative Biology, 2002

Research paper thumbnail of Left Ventricular Form and Function

Research paper thumbnail of Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations

Circulation, 1994

BACKGROUND We have previously described two distinct mutations in the beta-myosin heavy chain gen... more BACKGROUND We have previously described two distinct mutations in the beta-myosin heavy chain gene with markedly different clinical presentations and outcome: The 908Leu-->Val mutation was associated with a low disease penetrance and a benign prognosis. In contrast, the 403Arg-->Gln mutation in a Caucasian kindred was associated with a 100% disease penetrance and high incidence of sudden cardiac death. Recently, another mutation, 606Val-->Met, has been reported to be associated with "near normal survival" and offered as evidence for the benign nature of neutral charge substitutions. METHODS AND RESULTS We report (1) a large kindred (245 family members at risk of inheriting the disease gene) with a 256Gly-->Glu mutation characterized by a similar disease penetrance in adults and in children (56% and 60%, respectively) and a cumulative sudden cardiac death rate of only 2% at 50 years of age, (2) a kindred with the 606Val-->Met mutation with four sudden cardiac...

Research paper thumbnail of The Overall Pattern of Cardiac Contraction Depends on a Spatial Gradient of Myosin Regulatory Light Chain Phosphorylation

Cell, 2001

1984; Beyar and Sideman, 1986). It has been previously observed, but not fully understood, that t... more 1984; Beyar and Sideman, 1986). It has been previously observed, but not fully understood, that the epicardial fibers dominate the endocardial fibers (Buchalter et al., 1990; Maier et al., 1992; Young et al., 1994). That is, despite the counter-helical orientation of the endocar

Research paper thumbnail of Cross-Bridge Populations and the Biphasic Time Course of Muscle Relaxation

Biophysical Journal, 2011

the C-terminal domain, thus causing no activation of ATPase activity. With the addition of 1 mM N... more the C-terminal domain, thus causing no activation of ATPase activity. With the addition of 1 mM NEMS-1 the ATPase activation decreased from~225% at pCa 7.5 to~85% at pCa 6.5. The data suggest that in the absence of Ca 2þ at site II strong-binding myosin crossbridges cause opening of more active sites on the thin filament if the C-domain is occupied by Mg 2þ rather than Ca 2þ. This effect could be relevant to the contraction-relaxation kinetics of cardiac muscle. As Ca 2þ dissociates from site II during the relaxing phase of the cardiac cycle, residual Ca 2þ bound at the C-terminus might facilitate the switching off of the thin filament and the detachment of crossbridges from actin.

Research paper thumbnail of Genetic evidence of dissociation (generational skips) of electrical from morphologic forms of hypertrophic cardiomyopathy

The American Journal of Cardiology, 1990

Research paper thumbnail of When Is a Fly in the Ointment a Solution and not a Problem?

Circulation Research, 2006

Research paper thumbnail of The human genes for GM-CSF and IL-3 are closely linked in tandem on chromosome 5

As demonstrated by long-range mapping of restriction endonuclease recognition sequences and genom... more As demonstrated by long-range mapping of restriction endonuclease recognition sequences and genomic cloning. we found that the human genes encoding interleukin 3 (II 3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) are tandemly arrayed on the long arm of chro-mosome 5. separated by 9 kilobases (kb) of DNA. This close physical linkage of genes with similar structure and biologic function suggests that these cytokines may have evolved T HE CONTINUOUS production of mature blood cells from progenitor cells resident in the bone marrow is a complex process that is regulated in part by many different growth factors and cytokines including the hematopoietic colony-stimulating factors (CSFs),”2 erythropoietin (Epo),3 and the interleukins (IL I through IL 6).1.2 Despite the relatedness in function of the different cytokines, many of

Research paper thumbnail of Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles origi... more Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at:

Research paper thumbnail of Immunoinformatic Analysis of T- and B-Cell Epitopes for SARS-CoV-2 Vaccine Design

Vaccines

Currently, there is limited knowledge about the immunological profiles of Severe Acute Respirator... more Currently, there is limited knowledge about the immunological profiles of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We used computer-based immunoinformatic analysis and the newly resolved 3-dimensional (3D) structures of the SARS-CoV-2 S trimeric protein, together with analyses of the immunogenic profiles of SARS-CoV, to anticipate potential B-cell and T-cell epitopes of the SARS-CoV-2 S protein for vaccine design, particularly for peptide-driven vaccine design and serological diagnosis. Nine conserved linear B-cell epitopes and multiple discontinuous B-cell epitopes composed of 69 residues on the surface of the SARS-CoV-2 trimeric S protein were predicted to be highly antigenic. We found that the SARS-CoV-2 S protein has a different antigenic profile than that of the SARS-CoV S protein due to the variations in their primary and 3D structures. Importantly, SARS-CoV-2 may exploit an immune evasion mechanism through two point mutations in the critical and conserved...

Research paper thumbnail of The human genes for GM-CSF and IL 3 are closely linked in tandem on chromosome 5

Blood, 1988

As demonstrated by long-range mapping of restriction endonuclease recognition sequences and genom... more As demonstrated by long-range mapping of restriction endonuclease recognition sequences and genomic cloning, we found that the human genes encoding interleukin 3 (IL 3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) are tandemly arrayed on the long arm of chromosome 5, separated by 9 kilobases (kb) of DNA. This close physical linkage of genes with similar structure and biologic function suggests that these cytokines may have evolved from a common ancestral gene. This linkage in evolution of two relatively divergent genes further implies that some of the other lymphokine and cytokine genes that appear to share as much or more sequence similarity than do IL 3 and GM-CSF may be distantly related members of a cytokine gene family.

Research paper thumbnail of Common miR-590 Variant rs6971711 Present Only in African Americans Reduces miR-590 Biogenesis

PLOS ONE, 2016

MicroRNAs (miRNAs) are recognized as important regulators of cardiac development, hypertrophy and... more MicroRNAs (miRNAs) are recognized as important regulators of cardiac development, hypertrophy and fibrosis. Recent studies have demonstrated that genetic variations which cause alterations in miRNA:target interactions can lead to disease. We hypothesized that genetic variations in miRNAs that regulate cardiac hypertrophy/fibrosis might be involved in generation of the cardiac phenotype in patients diagnosed with hypertrophic cardiomyopathy (HCM). To investigate this question, we Sanger sequenced 18 miRNA genes previously implicated in myocyte hypertrophy/fibrosis and apoptosis, using genomic DNA isolated from the leukocytes of 199 HCM patients. We identified a single nucleotide polymorphism (rs6971711, C57T SNP) at the 17th position of mature miR-590-3p (= 57th position of pre-miR-590) that is common in individuals of African ancestry. SNP frequency was higher in African American HCM patients (n = 55) than ethnically-matched controls (n = 100), but the difference was not statistically significant (8.2% vs. 6.5%; p = 0.5). Using a cell culture system, we discovered that presence of this SNP resulted in markedly lower levels of mature miR-590-5p (39 ± 16%, p<0.003) and miR-590-3p (20 ± 2%, p<0.003), when compared with wild-type (WT) miR-590, without affecting levels of pri-miR-590 and pre-miR-590. Consistent with this finding, the SNP resulted in reduced target suppression when compared to WT miR-590 (71% suppression by WT vs 60% suppression by SNP, p<0.03). Since miR-590 can regulate TGF-β, Activin A and Akt signaling, SNP-induced reduction in miR-590 biogenesis could influence cardiac phenotype by de-repression of these signaling pathways. Since the SNP is only present in African Americans, population studies in this patient

Research paper thumbnail of The in vitro motility activity of -cardiac myosin depends on the nature of the -myosin heavy chain gene mutation in hypertrophic cardiomyopathy

J Muscle Res Cell Motil, 1997

Research paper thumbnail of Mechanistic role of movement and strain sensitivity in muscle contraction

Proceedings of the National Academy of Sciences of the United States of America, Jan 14, 2009

Tension generation can be studied by applying step perturbations to contracting muscle fibers and... more Tension generation can be studied by applying step perturbations to contracting muscle fibers and subdividing the mechanical response into exponential phases. The de novo tension-generating isomerization is associated with one of these phases. Earlier work has shown that a temperature jump perturbs the equilibrium constant directly to increase tension. Here, we show that a length jump functions quite differently. A step release (relative movement of thick and thin filaments) appears to release a steric constraint on an ensemble of noncompetent postphosphate release actomyosin cross-bridges, enabling them to generate tension, a concentration jump in effect. Structural studies [Taylor KA, et al. (1999) Tomographic 3D reconstruction of quick-frozen, Ca(2+)-activated contracting insect flight muscle. Cell 99:421-431] that map to these kinetics indicate that both catalytic and lever arm domains of noncompetent myosin heads change angle on actin, whereas lever arm movement alone mediates ...

Research paper thumbnail of The molecular biology and pathophysiology of hypertrophic cardiomyopathy due to mutations in the beta myosin heavy chains and the essential and regulatory light chains

Advances in experimental medicine and biology, 1998

Hypertrophic cardiomyopathy (HCM) is perhaps the most common cause of inherited sudden death in o... more Hypertrophic cardiomyopathy (HCM) is perhaps the most common cause of inherited sudden death in otherwise healthy young individuals. There are presently seven known genes in which mutations have been shown to cause the disease. The first identified disease gene was beta myosin heavy chain (BMHC). Our laboratory has identified 32 distinct BMHC gene mutations in 62 kindreds after screening representatives of over 400 kindreds. Virtually all but one of approximately 50 known mutations are restricted to the head or head-rod junction region of the molecule. We have used the mutant alleles of the BMHC gene to demonstrate that both mutant message and protein is present in the skeletal muscle of patients with HCM. Muscle biopsies from patients with identified BMHC mutations show abnormal histology. Isolated myosin and skinned fibers from these patients have abnormal mechanical properties. The BMHC gene mutations are clustered in 4 regions of the myosin head. Because one of these regions is ...

Research paper thumbnail of Mechanistic role of movement and strain sensitivity in muscle contraction

Proceedings of The National Academy of Sciences, 2009

Tension generation can be studied by applying step perturbations to contracting muscle fibers and... more Tension generation can be studied by applying step perturbations to contracting muscle fibers and subdividing the mechanical response into exponential phases. The de novo tension-generating isomerization is associated with one of these phases. Earlier work has shown that a temperature jump perturbs the equilibrium constant directly to increase tension. Here, we show that a length jump functions quite differently. A