Disease relevance of Myl4

• A DNA fragment from bp -36 to -597 confers tissue- and stage-specific activity to the herpes simplex virus thymidine kinase promoter in both orientations, showing that the skeletal muscle-specific regulation of the MLC1A gene is under the control of a muscle-specific enhancer which extends into the proximal promoter region [1].
• Atrial arrhythmia could not be induced in KO mice [2].
• The mean duration of atrial tachycardia was 126 +/- 384 s [3].
• Profound bradycardia heralded atrial and ventricular dilatation, dysfunction, and fibrosis [4].
• Atrial bradycardia and AV block were already present 3 weeks after birth [4].

High impact information on Myl4

• Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium [5].
• The cardiac defects include atrial and ventricular septal defects, overriding aorta, double-outlet right ventricle, persistent truncus arteriosus and right-sided aortic arches [6].
• Guanylate cyclase has been strongly implicated as a cell-surface receptor on spermatozoa for a chemotactic peptide, and on various other cells as a receptor for atrial natriuretic peptides [7].
• In contrast, isoprenaline, fenoterol and salbutamol are less potent as stimulants of lipolysis than as stimulants of atrial rate or tracheal relaxation [8].
• This resulted in increased basal myocardial adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo; these parameters at baseline in the transgenic animals were equal to those observed in control animals maximally stimulated with isoproterenol [9].

Chemical compound and disease context of Myl4

• Atrial tachycardia and fibrillation were inducible in one mouse at baseline electrophysiology study and eleven of fourteen mice after carbamyl choline injection [3].
• Reinduction of atrial tachycardia after administration of atropine was not possible [3].
• Gene dose-dependent atrial arrhythmias, heart block, and brady-cardiomyopathy in mice overexpressing A(3) adenosine receptors [4].
• The sinus cycle length and refractory periods prolonged on procainamide or quinidine, but no tachyarrhythmias could be induced with atrial or ventricular programmed stimulation [10].
• p-Hydroxy-N-(2-diethylaminoethyl)benzamide (2), the p-hydroxy isostere of procainamide (1), shows antiarrhythmic activity against acontine-induced atrial arrhythmia and lowers mean arterial blood pressure after iv infusion in dogs [11].

Biological context of Myl4

• Enzymatically disaggregated atrial and ventricular mouse myocytes were field-stimulated at multiple frequencies, and mechanical properties and calcium kinetics were studied by use of video edge detection and FURA 2-AM, respectively [12].
• The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression [13].
• Transient transfection assays of mouse skeletal muscle cell lines with DNA constructs containing MLC1A promoter fragments fused to the chloramphenicol acetyltransferase (CAT) gene show that the first 630 bp of the promoter is sufficient to direct expression of the reporter gene during myotube formation [1].
• Using a lacZ/knock-in mouse and three lines of transgenic mouse harboring various CARP promoter/lacZ reporters, we have identified distinct 5' cis regulatory elements of the gene that can direct heart segment-specific transgene expression, such as atrial versus ventricular and left versus right [14].
• Downregulation of atrial markers during cardiac chamber morphogenesis is irreversible in murine embryos [15].

Anatomical context of Myl4

• Electron microscopy revealed a cardiomyocyte-like ultrastructure, including typical sarcomeres, a centrally positioned nucleus, and atrial granules [16].
• This process is complete by 10.5 d p.c. During this time, MHC alpha mRNA levels decrease in ventricular muscle cells but continue to be expressed at high levels in atrial muscle cells [17].
• Between 7.5 and 8 d post coitum (p.c.), the newly formed cardiac tube begins to express MHC alpha, MHC beta, MLC1 atrial (MLC1A), and MLC1 ventricular (MLC1V) gene transcripts at high levels throughout the myocardium [17].
• Mutations within the CArG box distinguish between the binding of this complex and binding of SRF; only SRF binding is directly involved in the specific regulation of the MLC1A gene in skeletal muscle cell lines [1].
• In fetuses treated with beta-bungarotoxin and which therefore develop in the absence of functional nerve, MLC1A and MLC1F undergo normal transitions but MLC3F mRNA accumulation is significantly retarded [18].

Associations of Myl4 with chemical compounds

• The NH2-terminal region of MLC1A/MLC1emb, thought to be involved in the actomyosin interaction, shows conservation with MLC1V but not with MLC1F suggesting a shared functional domain in these cardiac isoforms [19].
• RESULTS: Atrial fibrillation lasting for a mean of 5.7+/-11 min was initiated in 10 of 14 WT mice in the presence of carbachol, but not in the absence of carbachol [2].
• No significant changes in ANP or atrial BNP mRNA were found [20].
• Reduced plasma epinephrine and corticosterone levels and adrenal medullary EGR-1 protein levels in CRH knockout versus WT mice during stress indicate that the HPA axis plays a crucial role in regulation of the PNMT gene expression in these organs.Cardiac atrial PNMT gene expression with stress is also dependent on intact HPA axis [21].
• We hypothesize that retinoic acid provides a critical signal mediated through the RXR alpha pathway that is required to allow progression of development of the ventricular region of the heart from its early atrial-like form to the thick-walled adult ventricle [22].

Regulatory relationships of Myl4

• Myosin light chain 1 atrial isoform (MLC1A) is expressed in pre-B cells under control of the BOB.1/OBF.1 coactivator [23].

Other interactions of Myl4

• In contrast, the cardiac MLC1A mRNA is initially more abundant than that encoding the skeletal MLC1F isoform [24].
• For example, in the myotome, when myosin light chain genes are initially transcribed, hybridization signal with probe for MLC1A mRNA is greater than that with probe for MLC1F transcripts, whereas the relative intensity of signal with these same probes is reversed in the hindlimb [25].
• Among these is an "MLC-sequence" (CCTTTTATAG) common to all MLC genes, including those of chick and rat, and a "cardiac sequence" common to the mouse MLC1A, MLC1V and alpha-cardiac actin genes expressed in the heart [26].
• Consistent with this conclusion is the observation that transcriptional induction of the endogenous MLC1A gene by BOB.1/OBF.1 requires de novo protein synthesis [23].
• Here, we identified three additional previously uncharacterized distal enhancer modules of Nkx2-5: UH6, which directed transgene expression in the right ventricle, interventricular septum, and atrial ventricular canal; UH5, which directed expression in both atria; and UH4, which directed transgene expression in tongue muscle [27].

Analytical, diagnostic and therapeutic context of Myl4

• We have used transgenesis to replace the ventricular isoform of the essential myosin light chain with the atrial isoform [28].
• In situ hybridization, with 35S-labeled antisense cRNAs, demonstrates the versatility of primary myotubes in that transcripts for (1) alpha-cardiac and alpha-skeletal actin, (2) MHCembryonic, MHCperinatal and MHC beta/slow, and (3) MLC1A, MLC1F and MLC3F are detectable at 14 days gestation [25].
• Northern blot analysis revealed that the expression of mouse sarcolipin mRNA was most abundant in the atria and was undetectable in the ventricles, indicating an atrial chamber-specific expression pattern [29].
• Northern blot, reverse transcriptase-linked polymerase chain reaction, RNase protection, and Western blot analysis revealed atrial restricted expression in the adult mouse heart, very low levels in aorta, and no detectable expression in ventricle, skeletal muscle, uterus, or liver [30].
• A six-lead ECG was recorded from surface limb leads, and an octapolar electrode catheter was inserted via jugular vein cutdown approach for simultaneous atrial and ventricular endocardial recording and pacing [3].

References