Recombinant Mouse Myosin-binding protein H-like (Mybphl) is a protein that plays a crucial role in cardiac function, particularly in the regulation of conduction within the atria and ventricular conduction systems . This protein is primarily expressed in atrial tissue and exists in two isoforms, with isoform 2 being almost exclusively restricted to the atria . The recombinant form of Mybphl is used in research to study its functions and implications in cardiac diseases.
Mybphl is predominantly expressed in the atria, with some expression in discrete subsets of the ventricle, particularly in areas associated with the ventricular conduction system . Immunofluorescence studies have identified Mybphl-positive ventricular cardiomyocytes near the atrioventricular node and in a subset of Purkinje fibers, suggesting its role in both atrial and ventricular conduction .
Mybphl is associated with myofilament structures in atrial tissue and plays a role in regulating cardiac conduction . Loss or mutations in the Mybphl gene have been linked to dilated cardiomyopathy, atrial and ventricular arrhythmias, and atrial enlargement . The protein's absence leads to increased heterogeneity of calcium release and disorganization of ryanodine receptors, contributing to arrhythmias .
Mybphl has been identified as a promising biomarker for predicting atrial myocardial damage. After atrial injury, such as that caused by cryo- or radiofrequency ablation, Mybphl is rapidly released into the bloodstream, where its levels remain elevated for up to 24 hours . This release is correlated with established biomarkers like CK-MB, indicating its potential as a specific marker for atrial damage .
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Myosin-binding protein H-like (MyBP-H-like) plays a critical role in cardiac function. It appears to regulate conduction within the atria and ventricular conduction systems.
Mybphl is a sarcomeric protein that shares sequence and domain homology with myosin-binding protein C (MyBP-C). It consists of 4 globular domains: 2 immunoglobulin-like (Ig-like) and 2 fibronectin-III-like (Fn3-like) domains connected in series by flexible linkers . Unlike MyBP-C, Mybphl has a long (78–134 amino acid), proline-alanine rich, unstructured domain that resembles the very N-terminus of skeletal muscle MyBP-Cs .
Expression patterns show Mybphl is highly expressed in the atria with only scarce, distinct clusters of Mybphl-positive cells within and surrounding the ventricular conduction system . Immunofluorescence microscopy of normal adult mouse ventricles has identified Mybphl-positive ventricular cardiomyocytes that co-localize with the ventricular conduction system marker contactin-2 near the atrioventricular node and in a subset of Purkinje fibers . This localization pattern suggests Mybphl plays a specialized role in specific cardiac regions.
Constitutive knockout of Mybphl in mice causes multiple cardiac abnormalities including:
Atrial dilation and arrhythmia
Dilated cardiomyopathy (DCM)
Atrioventricular block and atrial bigeminy
Shorter atrial relative refractory period
Atrial tachycardia following burst pacing
At the cellular level, calcium transient analysis of isolated Mybphl-null atrial cardiomyocytes demonstrates increased heterogeneity of calcium release and faster rates of calcium release compared to wild type controls . Super-resolution microscopy reveals ryanodine receptor disorganization in Mybphl heterozygous and homozygous null atrial cardiomyocytes . These findings help explain the observed arrhythmias and cardiac dysfunction at the organ level.
Conditional deletion of Mybphl produces distinct phenotypes depending on the timing and location of deletion:
Mice with conditional decrease of Mybphl in adulthood develop a hypertrophic phenotype with atrial contractile changes, increased total heart weight to body weight ratio, and increased heart rate variability
Deletion of Mybphl solely within the cardiac conduction system (using Contactin-2-Cre) trends toward mild hypercontractility, lower heart rates, and interventricular septal thickening
These data demonstrate that Mybphl is essential for proper cardiac function, and even minor alterations in protein levels can cause a diseased cardiac phenotype .
Several complementary imaging techniques provide comprehensive analysis of Mybphl localization:
Conditional knockout models can be generated using the following approach:
Create a conditional floxed Mybphl mouse line
Cross this line with specific Cre-recombinase expressing lines:
Allow temporal control over gene deletion to distinguish developmental from adult roles
Enable tissue-specific deletion to study Mybphl function in specific cardiac regions
Help avoid compensatory mechanisms that might develop in constitutive models
Validation of knockout efficiency should include protein quantification in target tissues and assessment of residual Mybphl-positive cells using immunofluorescence microscopy .
A comprehensive electrophysiological assessment should include:
Several mechanisms have been proposed based on current research:
Calcium handling abnormalities: Mybphl-null atrial cardiomyocytes show increased heterogeneity and faster rates of calcium release, which likely contributes to arrhythmogenesis
Subcellular structural disarray: Super-resolution microscopy reveals ryanodine receptor disorganization in Mybphl-deficient cardiomyocytes, suggesting disrupted excitation-contraction coupling
Conduction system development: The proximity of Mybphl-positive cells to the ventricular conduction system suggests Mybphl may influence conduction system development or function, explaining how a predominantly atrial expressed gene contributes to ventricular arrhythmias and dysfunction
Altered functional properties of specialized cardiomyocytes: Mybphl localization in discrete regions of the ventricle suggests it may provide nuanced tuning of specific cells critical for normal conduction
These mechanisms warrant further investigation, particularly to determine whether abnormalities arise from developmental defects or from dysregulation of adult cardiomyocyte function.
Recombinant Mybphl offers a powerful tool for investigating the molecular mechanisms of disease-associated mutations:
Generation of mutant constructs: Site-directed mutagenesis can be used to generate mouse Mybphl constructs mimicking human MYBPHL nonsense mutations reported in genomic databases like gnomAD
Validation and preparation: Plasmids should be sequenced by Sanger reaction and prepared using endo-free maxi prep kits for transfection quality
Functional analysis: Experiments can assess:
Proteomic analysis: Mass spectrometry approaches using systems like the Vanquish Neo UHPLC with an Orbitrap Eclipse Tribrid mass spectrometer can provide detailed characterization of mutant proteins and their interactions
This approach provides mechanistic insights into how genetic variants lead to cardiac dysfunction.
Investigating Mybphl in specialized cardiac cells presents several methodological challenges:
A comprehensive calcium handling assessment should include:
Research on Mybphl has significant clinical implications:
Genetic basis of cardiomyopathy: Mutations in human MYBPHL are linked to hereditary dilated cardiomyopathy, atrial fibrillation, and atrioventricular arrhythmias
Mechanistic insights: Understanding how Mybphl deficiency causes subcellular disarray and calcium handling abnormalities provides insights into pathogenic mechanisms of cardiac arrhythmias and cardiomyopathy
Developmental contributions: The potential role of Mybphl in cardiac development suggests some cardiac diseases may have developmental origins
Therapeutic targets: Identification of the molecular pathways affected by Mybphl deficiency could reveal new therapeutic targets for treating cardiac conduction disorders and cardiomyopathies
Future studies using conditional deletion of Mybphl in adult mice will help determine whether loss of Mybphl during development is required for disease or if MyBP-HL dynamically regulates adult cardiomyocytes such that its absence leads to the observed pathophysiology .