MYBPC

Myosin binding protein C (MyBPC) is a multi-domain protein with each region having a distinct functional role in muscle contraction. The central domains of MyBPC have often been overlooked due to their unclear roles. However, recent research shows promise in understanding their potential structural and regulatory functions. Understanding the central region of MyBPC is important because it may have specialized function that can be used as drug targets or for disease-specific therapies. In this review, we provide a brief overview of the evolution of our understanding of the central domains of MyBPC in regard to its domain structures, arrangement and dynamics, interaction partners, hypothesized functions, disease-causing mutations, and post-translational modifications...

Background and objectives Endothelial soluble lectin-type oxidized low-density lipoprotein receptor 1 (sLOX-1) recognizes oxidized low-density lipoprotein (LDL) and triggers downstream signaling leading to atherosclerosis. The objective of this study was to demonstrate the utility of sLOX-1 as a biomarker for detecting acute myocardial infarction (MI) and stable angina (SA) and to develop a diagnostic algorithm for distinguishing coronary vasospasm from coronary plaque rupture. Methods We enrolled 62 patients who underwent diagnostic coronary angiography (CAG) and 30 healthy controls (21 men and nine women) and measured sLOX-1, troponin I, and cardiac myosin-binding protein C (c-MyBPC) using commercial kits...

The MF30 monoclonal antibody, which binds to the myosin subfragment-2 (S2), was found to increase the extent of myofibril shortening. Yet, previous observations found no effect of this antibody on actin sliding over myosin during in vitro motility assays with purified proteins in which myosin binding protein C (MyBPC) was absent. MF30 is hypothesized to enhance the availability of myosin heads (subfragment-1 or S1) to bind actin by destabilizing the myosin S2 coiled-coil and sterically blocking S2 from binding S1...

Skeletal muscle, a highly complex muscle type in the eukaryotic system, is characterized by different muscle subtypes and functions associated with specific myosin isoforms. As a result, skeletal muscle is the target of numerous diseases, including distal arthrogryposes (DAs). Clinically, DAs are a distinct disorder characterized by variation in the presence of contractures in two or more distal limb joints without neurological issues. DAs are inherited, and up to 40% of patients with this condition have mutations in genes that encode sarcomeric protein, including myosin heavy chains, troponins, and tropomyosin, as well as myosin binding protein-C (MYBPC)...

Biotherapeutics are exposed to common transition metal ions such as Cu(II) and Fe(II) during manufacturing processes and storage. IgG1 biotherapeutics are vulnerable to reactive oxygen species (ROS) generated via the metal-catalyzed oxidation reactions. Exposure to these metal ions can lead to potential changes to structure and function, ultimately influencing efficacy, potency, and potential immunogenicity of the molecules. Here, we stress four biotherapeutics of the IgG1 subclass (trastuzumab, trastuzumab emtansine, anti-NaPi2b, and anti-NaPi2b-vc-MMAE) with two common pharmaceutically relevant metal-induced oxidizing systems, Cu(II)/ ascorbic acid and Fe(II)/ H2 O2 , and evaluated oxidation, size distribution, carbonylation, Fc effector functions, antibody-dependent cellular cytotoxicity (ADCC) activity, cell anti-proliferation and autophaghic flux...

Myosin binding protein-C (MyBP-C) is a sarcomeric protein which regulates the force of contraction in striated muscles. Mutations in the MYBPC family of genes, including slow skeletal ( MYBPC1 ), fast skeletal ( MYBPC2 ) and cardiac ( MYBPC3 ), can result in cardiac and skeletal myopathies. Nonetheless, their evolutionary pattern, pathogenicity and impact on MyBP-C protein structure remain to be elucidated. Therefore, the present study aimed to systematically assess the evolutionarily conserved and epigenetic patterns of MYBPC family mutations...

Heart failure is classified as heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF). Although several therapies have been demonstrated to improve outcomes in patients with HFrEF, none benefit patients with HFpEF. The molecular mechanism that results in HFpEF is unknown and has been impacted by the lack of animal models, and thus, we tested the hypothesis that metabolic and hypertensive stress would result in a rat model of HFpEF. Fischer 344 rats (6mo old) were fed a high fat diet and L-NAME in the drinking water for 4-weeks...

Mutations in the gene encoding cardiac myosin-binding protein-C (MyBPC), a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function, are a common cause for the development of hypertrophic cardiomyopathy. About 10% of carriers of the Δ25bp variant of MYBPC3 , which is common in individuals from South Asia, are also carriers of the D389V variant on the same allele. Compared with noncarriers and those with MYBPC3 Δ 25bp alone, indicators for the development of hypertrophic cardiomyopathy occur with increased frequency in MYBPC3 Δ 25bp/D389V carriers...

Diabetes doubles the risk of developing heart failure (HF). As the prevalence of diabetes grows, so will HF unless the mechanisms connecting these diseases can be identified. Methylglyoxal (MG) is a glycolysis by-product that forms irreversible modifications on lysine and arginine, called glycation. We previously found that myofilament MG glycation causes sarcomere contractile dysfunction and is increased in patients with diabetes and HF. The aim of this study was to discover the molecular mechanisms by which MG glycation of myofilament proteins cause sarcomere dysfunction and to identify therapeutic avenues to compensate...

Increased oxidative stress by reactive oxygen species (ROS) and reactive nitrogen species (RNS) is a major determinant of disuse-induced muscle atrophy. Muscle biopsies (thigh vastus lateralis, VL ) obtained from healthy male subjects enrolled in the Toulouse Cocktail bedrest (BR) study were used to assess efficacy of an antioxidant cocktail (polyphenols, omega-3, vitamin E, and selenium) to counteract the increased redox homeostasis and enhance the antioxidant defense response by using label-free LC-MS/MS and NITRO-DIGE (nitrosated proteins), qPCR, and laser confocal microscopy...

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The loss of cardiac myosin binding protein C (cMyBP-C) results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function in both constitutive and conditional cMyBP-C knockout ( MYBPC3 null) mice. It remains unclear whether the structural and functional phenotypes expressed in the MYBPC3 null mouse are reversible, which is an important question, since reduced expression of cMyBP-C is an important cause of hypertrophic cardiomyopathy in humans. To investigate this question, we generated a cardiac-specific transgenic mouse model using a Tet-Off inducible system to permit the controlled expression of WT cMyBP-C on the MYBPC3 null background...

Background Left ventricular noncompaction cardiomyopathy ( LVNC ) is a genetically and phenotypically heterogeneous disease. This study aims to investigate the genetic basis and genotype-phenotype correlations in a cohort of Chinese patients with LVNC . Methods and Results A total of 72 cardiomyopathy-associated genes were comprehensively screened in 83 adults and 17 children with LVNC by targeted sequencing. Pathogenicity of the detected variants was determined according to their prevalence and American College of Medical Genetics and Genomics recommendations...

Data presented in this article relates to the research article entitled "Whole length myosin binding protein C stabilizes myosin subfragment-2 (S2) flexibility as measured by gravitational force spectroscopy." (Singh et al., 2018) [1]. The data exhibits the purified skeletal myosin binding protein C (MyBPC) from rabbit back muscle was of slow skeletal type confirmed by chromatography and in unphosphorylated state based on its isoelectric point (pI) by chromatofocussing. The competitive enzyme linked immunosorbent assay (cELISA) data displayed the site specificity of polyclonal anti-S2 antibody to myosin S2...

The mechanical stability of the myosin subfragment-2 (S2) was tested with simulated force spectroscopy (SFS) and gravitational force spectroscopy (GFS). Experiments examined unzipping S2, since it required less force than stretching parallel to the coiled coil. Both GFS and SFS demonstrated that the force required to destabilize the light meromyosin (LMM) was greater than the force required to destabilize the coiled coil at each of three different locations along S2. GFS data also conveyed that the mechanical stability of the S2 region is independent from its association with the myosin thick filament using cofilaments of myosin tail and a single intact myosin...

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases and among the leading causes of sudden cardiac death (SCD) in the young. The cellular mechanisms leading to SCD in HCM are not well known. Prolongation of the action potential (AP) duration (APD) is a common feature predisposing hypertrophied hearts to SCD. Previous studies have explored the roles of inward Na+ and Ca2+ in the development of HCM, but the role of repolarizing K+ currents has not been defined. The objective of this study was to characterize the arrhythmogenic phenotype and cellular electrophysiological properties of mice with HCM, induced by myosin-binding protein C (MyBPC) knockout (KO), and to test the hypothesis that remodeling of repolarizing K+ currents causes APD prolongation in MyBPC KO myocytes...

In myocarditis and dilated cardiomyopathy (DCM) patients the immune system may play an important role in disease progression. In this study, we aimed to identify new antigens as a target for autoimmune response that might play a crucial role in these diseases. Therefore, a peptide-array was used to investigate antibody binding profiles in patients with autoimmune myocarditis or DCM compared to healthy controls and thus to identify disease relevant antigens. To analyze the pathogenicity of the identified antigens, an experimental autoimmune myocarditis (EAM) model was used...

BACKGROUND: Previous data suggest that mitral valve leaflets are elongated in hypertrophic cardiomyopathy (HCM), and mitral valve leaflet elongation may constitute a primary phenotypic expression of HCM. Our objective was to measure the length of mitral valve leaflets by cardiovascular magnetic resonance (CMR) in subjects with HCM caused by a Finnish founder mutation in the myosin-binding protein C gene (MYBPC3-Q1061X), carriers of the same mutation without left ventricular hypertrophy, as well as in unselected consecutive patients with HCM, and respective controls...

Myosin-binding protein C (MyBPC) in the muscle sarcomere interacts with several contractile and structural proteins. Mutations in the cardiac isoform (MyBPC-3) in humans, or animal knockout, are associated with cardiomyopathy. Function of the fast skeletal isoform (MyBPC-2) in living muscles is less understood. This question was addressed using zebrafish models, combining gene expression data with functional analysis of contractility and small-angle x-ray diffraction measurements of filament structure. Fast skeletal MyBPC-2B, the major isoform, was knocked down by >50% using morpholino antisense nucleotides...

β-adrenergic stimulation increases cardiac myosin binding protein C (MyBP-C) and troponin I phosphorylation to accelerate pressure development and relaxation in vivo, although their relative contributions remain unknown. Using a novel mouse model lacking protein kinase A-phosphorylatable troponin I (TnI) and MyBP-C, we examined in vivo haemodynamic function before and after infusion of the β-agonist dobutamine. Mice expressing phospho-ablated MyBP-C displayed cardiac hypertrophy and prevented full acceleration of pressure development and relaxation in response to dobutamine, whereas expression of phosphor-ablated TnI alone had little effect on the acceleration of contractile function in response to dobutamine...