Alpha and beta myosin isoforms and human atrial and ventricular contraction

Walklate, Jonathan; Ferrantini, Cecilia; Johnson, Chloe A; Tesi, Chiara; Poggesi, Corrado; Geeves, Michael A.

doi:10.1007/s00018-021-03971-y

Cited by 32 publications

(36 citation statements)

References 211 publications

(333 reference statements)

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“…We consider that the differential effect of MgADP on the leftward shift of pCa 50 between PLV and PLA results from a difference in the apparent binding affinity of MgADP to ventricular myosin vs. atrial myosin. It has indeed been reported that the equilibrium constant of the ADP-release during the cross-bridge cycling is higher for atrial myosin than ventricular myosin ( Wang et al, 2013 ; Walklate et al, 2021 ), thereby decreasing the apparent affinity of exogenously added MgADP.…”

Section: Discussionmentioning

confidence: 98%

Effects of omecamtiv mecarbil on the contractile properties of skinned porcine left atrial and ventricular muscles

et al. 2022

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Omecamtiv mecarbil (OM) is a novel inotropic agent for heart failure with systolic dysfunction. OM prolongs the actomyosin attachment duration, which enhances thin filament cooperative activation and accordingly promotes the binding of neighboring myosin to actin. In the present study, we investigated the effects of OM on the steady-state contractile properties in skinned porcine left ventricular (PLV) and atrial (PLA) muscles. OM increased Ca2+ sensitivity in a concentration-dependent manner in PLV, by left shifting the mid-point (pCa50) of the force-pCa curve (ΔpCa50) by ∼0.16 and ∼0.33 pCa units at 0.5 and 1.0 μM, respectively. The Ca2+-sensitizing effect was likewise observed in PLA, but less pronounced with ΔpCa50 values of ∼0.08 and ∼0.22 pCa units at 0.5 and 1.0 μM, respectively. The Ca2+-sensitizing effect of OM (1.0 μM) was attenuated under enhanced thin filament cooperative activation in both PLV and PLA; this attenuation occurred directly via treatment with fast skeletal troponin (ΔpCa50: ∼0.16 and ∼0.10 pCa units in PLV and PLA, respectively) and indirectly by increasing the number of strongly bound cross-bridges in the presence of 3 mM MgADP (ΔpCa50: ∼0.21 and ∼0.08 pCa units in PLV and PLA, respectively). It is likely that this attenuation of the Ca2+-sensitizing effect of OM is due to a decrease in the number of “recruitable” cross-bridges that can potentially produce active force. When cross-bridge detachment was accelerated in the presence of 20 mM inorganic phosphate, the Ca2+-sensitizing effect of OM (1.0 μM) was markedly decreased in both types of preparations (ΔpCa50: ∼0.09 and ∼0.03 pCa units in PLV and PLA, respectively). The present findings suggest that the positive inotropy of OM is more markedly exerted in the ventricle than in the atrium, which results from the strongly bound cross-bridge-dependent allosteric activation of thin filaments.

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Section: Discussionmentioning

confidence: 98%

Effects of omecamtiv mecarbil on the contractile properties of skinned porcine left atrial and ventricular muscles

et al. 2022

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“…There are two isoforms of myosin II heavy chains, the α and β isoforms, which have differential ATPase activity and are differentially expressed. Within the heart, the β-isoform is predominantly expressed in the ventricle, while the α-isoform is mainly found in the atrium ( Walklate et al, 2021 ).…”

Section: Single-molecule Studies Of Cardiovascular Diseasesmentioning

confidence: 99%

Application of optical tweezers in cardiovascular research: More than just a measuring tool

Yang

Zhu

et al. 2022

Front. Bioeng. Biotechnol.

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Recent advances in the field of optical tweezer technology have shown intriguing potential for applications in cardiovascular medicine, bringing this laboratory nanomechanical instrument into the spotlight of translational medicine. This article summarizes cardiovascular system findings generated using optical tweezers, including not only rigorous nanomechanical measurements but also multifunctional manipulation of biologically active molecules such as myosin and actin, of cells such as red blood cells and cardiomyocytes, of subcellular organelles, and of microvessels in vivo. The implications of these findings in the diagnosis and treatment of diseases, as well as potential perspectives that could also benefit from this tool, are also discussed.

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“…For example, the y 24 ion corresponding to C-terminal MLC-2v matched closely to the theoretical isotopic distribution for each cardiac chamber, and the experimentally-determined mass matches the theoretical mass with sub-ppm accuracy, indicating agreement with previously reported MLC-2v sequence ( Figure S15A ). Due to considerable sequence heterogeneity between MLC-2v and MLC-2a, 27 the observed fragment ions overwhelmingly indicate the presence of MLC-2v in the atrial chambers and do not match with a truncated or alternatively-spliced MLC-2a isoform. LC-MS/MS revealed key fragment ions matching to the reported sequence of MLC-2a, such as the y 25 ion shown across left and right atrial tissues ( Figure S15B ).…”

Section: Resultsmentioning

confidence: 95%

Top-down Proteomics of Myosin Light Chain Isoforms Define Chamber-Specific Expression in the Human Heart

Bayne

Rossler

Gregorich

et al. 2023

Preprint

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Myosin functions as the "molecular motor" of the sarcomere and generates the contractile force necessary for cardiac muscle contraction. Myosin light chains 1 and 2 (MLC-1 and -2) play important functional roles in regulating the structure of the hexameric myosin molecule. Each of these light chains has an "atrial" and "ventricular" isoform, so called because they are believed to exhibit chamber-restricted expression in the heart. However, recently the chamber-specific expression of MLC isoforms in the human heart has been questioned. Herein, we analyzed the expression of MLC-1 and -2 atrial and ventricular isoforms in each of the four cardiac chambers in adult non-failing donor hearts using top-down mass spectrometry (MS)-based proteomics. Strikingly, we detected an isoform thought to be ventricular, MLC-2v, in the atria and confirmed the protein sequence using tandem MS (MS/MS). For the first time, a putative deamidation post-translation modification (PTM) located on MLC-2v in atrial tissue was localized to amino acid N13. MLC-1v and MLC-2a were the only MLC isoforms exhibiting chamber-restricted expression patterns across all donor hearts. Importantly, our results unambiguously show that MLC-1v, not MLC-2v, is ventricle-specific in adult human hearts. Overall, top-down proteomics allowed us an unbiased analysis of MLC isoform expression throughout the human heart, uncovering previously unexpected isoform expression patterns and PTMs.

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Alpha and beta myosin isoforms and human atrial and ventricular contraction

Cited by 32 publications

References 211 publications

Effects of omecamtiv mecarbil on the contractile properties of skinned porcine left atrial and ventricular muscles

Effects of omecamtiv mecarbil on the contractile properties of skinned porcine left atrial and ventricular muscles

Application of optical tweezers in cardiovascular research: More than just a measuring tool

Top-down Proteomics of Myosin Light Chain Isoforms Define Chamber-Specific Expression in the Human Heart

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