Minigenes encoding N‐terminal domains of human cardiac myosin light chain‐1 improve heart function of transgenic rats

Haase, Hannelore; Dobbernack, Gisela; Tünnemann, Gisela; Karczewski, Peter; Cardoso, M. Cristina; Petzhold, Daria; Schlegel, Wolfgang-Peter; Lutter, Steffen; Pierschalek, Petra; Behlke, Joachim; Morano, Ingo

doi:10.1096/fj.05-5414com

Cited by 29 publications

(29 citation statements)

References 35 publications

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“…Synthetic NH 2 -terminal peptides revealed specific actin binding with a significantly lower dissociation constant for the ELC v compared with the ELC a . As was demonstrated, the expression of NH 2 -terminal human ELC peptides in transgenic rats correlated positively with improvements of the intrinsic contractile state (force generation and relaxation) in isolated perfused hearts (31).…”

Section: Transgenic Animal Models For Elcmentioning

confidence: 58%

“…Similar aspects of the ELC-actin interaction in transgenic animal models were addressed in a recent study by Hasse et al (31). The authors investigated whether the expression of NH 2 -terminal peptides of cardiac ELC could improve the intrinsic contractility at the whole heart level.…”

Section: Transgenic Animal Models For Elcmentioning

confidence: 80%

“…However, no alterations in either unloaded shortening or maximum shortening velocities were observed when muscle strips were not compressed (80). A recent study by Haase et al (31) showed that the expression of NH 2 -terminal human ELC peptides in transgenic rats correlated positively with improvements in the intrinsic contractile state of isolated perfused hearts.…”

Section: Function Of Nh 2 -Terminus Of Elcmentioning

confidence: 97%

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Myosin essential light chain in health and disease

Hernandez¹,

Jones²,

Guzman³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

115

113

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The essential light chain of myosin (ELC) is known to be important for structural stability of the ␣-helical lever arm domain of the myosin head, but its function in striated muscle contraction is poorly understood. Two ELC isoforms are expressed in fast skeletal muscle, a long isoform and its NH 2-terminal ϳ40 amino acid shorter counterpart, whereas only the long ELC is observed in the heart. Biochemical and structural studies revealed that the NH 2-terminus of the long ELC can make direct contacts with actin, but the effects of the ELC on the affinity of myosin for actin, ATPase, force, and the kinetics of force generating myosin cross-bridges are inconclusive. Myosin containing the long ELC has been shown to have slower cross-bridge kinetics than myosin with the short isoform. A difference was also reported among myosins with long isoforms. Increased shortening velocity was observed in atrial compared with ventricular muscle fibers. The common findings suggest that ELC provides the fine tuning of the myosin motor function, which is regulated in an isoform and tissue-dependent manner. The functional importance of the ELC is further implicated by the discovery of ELC mutations associated with Familial Hypertrophic Cardiomyopathy. The pathological phenotypes vary in severity, but more notably, almost all ELC mutations result in sudden cardiac death at a young age. This review summarizes the functional roles of striated muscle ELC in normal healthy muscle and in disease. Transgenic animal models and phenotypic characterization of ELC-mediated remodeling of the heart are also discussed.cross-bridge kinetics; striated muscle contraction; familial hypertrophic cardiomyopathy; sarcomeric mutations; failing heart; sudden cardiac death STRIATED MUSCLE MYOSIN

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Section: Transgenic Animal Models For Elcmentioning

confidence: 58%

Section: Transgenic Animal Models For Elcmentioning

confidence: 80%

Section: Function Of Nh 2 -Terminus Of Elcmentioning

confidence: 97%

See 1 more Smart Citation

Myosin essential light chain in health and disease

Hernandez¹,

Jones²,

Guzman³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

115

113

View full text Add to dashboard Cite

show abstract

“…13 In summary, hearts from anesthetized (30 mg kg À1 sodium chloralhydrate) and heparinized (3000 U kg À1 ) rats were rapidly excised after thoracotomy and arrested in 4 1C cold modified Krebs-Henseleit solution containing 118.0 mmol l À1 NaCl, 4.7 mmol l À1 KCl, 1.5 mmol l À1 CaCl 2 , 2.1 mmol l À1 MgSO 4 , 24.7 mmol l À1 NaHCO 3 , 0.06 mmol l À1 EDTA, 0.23 mmol l À1 KH 2 PO 4 , 11.1 mmol l À1 glucose and 1.0 mmol l À1 albumin. KrebsHenseleit solution was prepared at the time of the experiment and equilibrated with a mixture of 95% O 2 and 5% CO 2 yielding a pH of 7.4.…”

Section: Animalsmentioning

confidence: 99%

Adipocyte-derived factors suppress heart contraction

et al. 2010

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Background: Obesity is strongly associated with cardiovascular diseases including systemic hypertension, coronary artery disease and heart failure. Despite several investigations the pathophysiological mechanisms involved remain unclear. We have previously shown that adipose tissue exerts a highly potent activity with an acute depressant effect on cardiomyocytes, thus suggesting direct involvement of adipose tissue in the development of heart dysfunction. Objective and Design: This study investigates the effects of adipocyte factors obtained from subcutaneous adipose tissue on the whole cardiac function by using isolated perfused rat hearts in a Langendorff mode. We recorded changes in coronary flow, developed isovolumetric left ventricular pressure, contraction rate and relaxation rate. Results: We observed a significant decrease in heart contractility parameters as well as in coronary flow within a few seconds of incubation with adipocyte factors. The cardiodepressant effects could not be blocked by the nonselective cyclooxygenase-inhibitor indomethacin. Human adipocytes release tumor necrosis factor-a, interleukin-6 (IL-6) and IL-1b into extracellular medium. These cytokines were tested for their potential effect but were, however, not responsible for the cardiodepressant effect observed. Conclusion: These data indicate that human adipocytes secrete factors with a strong acute depressant effect on cardiac force generation and coronary flow due to contraction of the coronary vessels, thus suggesting a direct role of adipose tissue in the pathogenesis of cardiac dysfunction.

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“…1). Use of this dabcyl-labeled peptide, designated ANT, was inspired by previous reports showing that the first 13 amino acid residues of NTE are important regulators of the actin-myosin interaction (16) and affect contractility of muscle cells (17). A key advantage of ANT, over our previously used acceptor-labeled myosin (4), is that it can be synthesized and purified in large quantity, thus facilitating large-scale high-throughput screening (HTS).…”

mentioning

confidence: 99%

High-throughput screen, using time-resolved FRET, yields actin-binding compounds that modulate actin–myosin structure and function

Guhathakurta

Próchniewicz

Grant

et al. 2018

Journal of Biological Chemistry

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We have used a novel time-resolved FRET (TR-FRET) assay to detect small-molecule modulators of actin-myosin structure and function. Actin-myosin interactions play crucial roles in the generation of cellular force and movement. Numerous mutations and post-translational modifications of actin or myosin disrupt muscle function and cause life-threatening syndromes. Here, we used a FRET biosensor to identify modulators that bind to the actin-myosin interface and alter the structural dynamics of this complex. We attached a fluorescent donor to actin at Cys-374 and a nonfluorescent acceptor to a peptide containing the 12 N-terminal amino acids of the long isoform of skeletal muscle myosin's essential light chain. The binding site on actin of this acceptor-labeled peptide (ANT) overlaps with that of myosin, as indicated by () a similar distance observed in the actin-ANT complex as in the actin-myosin complex and () a significant decrease in actin-ANT FRET upon binding myosin. A high-throughput FRET screen of a small-molecule library (NCC, 727 compounds), using a unique fluorescence lifetime readout with unprecedented speed and precision, showed that FRET is significantly affected by 10 compounds in the micromolar range. Most of these "hits" alter actin-activated myosin ATPase and affect the microsecond dynamics of actin detected by transient phosphorescence anisotropy. We conclude that the actin-ANT TR-FRET assay enables detection of pharmacologically active compounds that affect actin structural dynamics and actomyosin function. This assay establishes feasibility for the discovery of allosteric modulators of the actin-myosin interaction, with the ultimate goal of developing therapies for muscle disorders.

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Minigenes encoding N‐terminal domains of human cardiac myosin light chain‐1 improve heart function of transgenic rats

Cited by 29 publications

References 35 publications

Myosin essential light chain in health and disease

Myosin essential light chain in health and disease

Adipocyte-derived factors suppress heart contraction

High-throughput screen, using time-resolved FRET, yields actin-binding compounds that modulate actin–myosin structure and function

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