Hybrid Logistic Characterization of Isometric Twitch Force Curve of Isolated Ferret Right Ventricular Papillary Muscle.

Missense mutations in alpha-tropomyosin (TPM1) can lead to development of hypertrophic (HCM) or dilated cardiomyopathy (DCM). HCM mutation E62Q and DCM mutation E54K have previously been studied extensively in experimental systems ranging from in vitro biochemical assays to animal models, although some conflicting results have been found. We undertook a detailed multi-scale assessment of these mutants that included atomistic simulations, regulated in vitro motility (IVM) assays, and finally physiologically relevant human engineered heart tissues. In IVM assays, E62Q previously has shown increased Calcium sensitivity. New molecular dynamics data shows mutation-induced changes to tropomyosin dynamics and interactions with actin and troponin. Human engineered heart tissues (EHT) were generated by seeding iPSC-derived cardiomyocytes engineered using CRISPR/CAS9 to express either E62Q or E54K cardiomyopathy mutations. After two weeks in culture, E62Q EHTs showed a drastically hypercontractile twitch force and significantly increased stiffness while displaying little difference in twitch kinetics compared to wild-type isogenic control EHTs. On the other hand, E54K EHTs displayed hypocontractile isometric twitch force with faster kinetics, impaired length-dependent activation and lowered stiffness. Given these contractile abnormalities, we hypothesized that small molecule myosin modulators to appropriately activate or inhibit myosin activity would restore E54K or E62Q EHTs to normal behavior. Accordingly, E62Q EHTs were treated with 0.5μM mavacamten (to remedy hypercontractility) and E54K EHTs with 0.5 μM danicamtiv (to remedy hypocontractility) for 4 days, followed by a 1 day washout period. Upon contractility testing, it was observed that the drugs were able to reverse contractile phenotypes observed in mutant EHTs and restore contractile properties to levels resembling those of the untreated wild type group. The computational, IVM and EHT studies provide clear evidence in support of the hyper- vs. hypo-contractility paradigm as a common axis that distinguishes HCM and DCM TPM1 mutations. Myosin modulators that directly compensate for underlying myofilament aberrations show promising efficacy in human in vitro systems.

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Logistic Time Constant of Isometric Relaxation Force Curve of Ferret Ventricular Papillary Muscle. Reliable Index of Lusitropism.

The Japanese Journal of Physiology ◽

10.2170/jjphysiol.50.479 ◽

2000 ◽

Vol 50 (5) ◽

pp. 479-487 ◽

Cited By ~ 11

Author(s):

Ju Mizuno ◽

Junichi Araki ◽

Takeshi Mikane ◽

Satoshi Mohri ◽

Takeshi Imaoka ◽

...

Keyword(s):

Time Constant ◽

Papillary Muscle ◽

Reliable Index ◽

Force Curve ◽

Relaxation Force

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Morphometric Study of Tricuspid Valve Annulus and Right Ventricular Papillary Muscle: A Cadaveric Study from Marathwada Region

Indian Journal of Anatomy ◽

10.21088/ija.2320.0022.8319.10 ◽

2019 ◽

Vol 8 (3) ◽

pp. 197-203

Author(s):

Mukta Pande ◽

◽

Shivaji Sukre ◽

Pratima Kulkarni ◽

◽

...

Keyword(s):

Right Ventricular ◽

Tricuspid Valve ◽

Papillary Muscle ◽

Cadaveric Study ◽

Morphometric Study ◽

Tricuspid Valve Annulus ◽

Valve Annulus

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Force reduction uncoupled from pH and H2PO 4 − in rat gastrocnemius in vivo with continuous 2-Hz stimulation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.2.r511 ◽

2001 ◽

Vol 281 (2) ◽

pp. R511-R518 ◽

Cited By ~ 6

Author(s):

Julie H. Cieslar ◽

Geoffrey P. Dobson

Keyword(s):

Relaxation Time ◽

Atp Hydrolysis ◽

Nerve Impulse ◽

Force Transducer ◽

Sprague Dawley ◽

Glycogen Depletion ◽

Cytosolic Ph ◽

Twitch Force ◽

Isometric Twitch

The aim of this study was to examine the effect of the products of ATP hydrolysis on the fatigue process in rat gastrocnemius in vivo. Adult male Sprague-Dawley rats (300–400 g) were anesthetized and ventilated in a custom-built cradle fitted with a force transducer that could be placed into a 7-T NMR magnet. The muscle was stimulated continuously at 2 Hz for 20 min ( n = 7). Isometric twitch force increased in the first 4 min of stimulation accompanied by changes in twitch duration (20% increase in relaxation time). Prolonged relaxation was associated with changes in cytosolic pH (6.91 to 6.58), lactate (1.8 to 12.6 μmol/g wet wt), and H2PO[Formula: see text] (7.57 to 13.99 mM). After 4 min, relaxation time, pH, lactate, and H2PO[Formula: see text] returned toward control values as twitch force progressively decreased. No correlation was found between force decline (or twitch broadening) and total phosphate (3 to 23 mM), free [ADP] (18 to 95 μM), free [Mg2+] (0.58 to 0.96 mM), or free energy of ATP hydrolysis (−65 to −55 kJ/mol). We conclude that force decline is not due to increased pH and/or H2PO[Formula: see text] but to fatigue of the fast-twitch fibers, possibly linked to glycogen depletion and/or failure of nerve impulse transmission in these fibers.

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The Morphology of Right Ventricular Papillary Muscle from Rats Exposed to 28 Days of Hypoxia

Clinical Science ◽

10.1042/cs078005p ◽

1990 ◽

Vol 78 (s22) ◽

pp. 5P-5P

Author(s):

SV Baudouin ◽

N Darius ◽

NT Bateman

Keyword(s):

Right Ventricular ◽

Papillary Muscle

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Contractile and Ca2+-handling properties of the right ventricular papillary muscle in the late-gestation sheep fetus

Journal of Applied Physiology ◽

10.1152/japplphysiol.00214.2006 ◽

2006 ◽

Vol 101 (3) ◽

pp. 728-733 ◽

Cited By ~ 7

Author(s):

T. N. Spencer ◽

K. J. Botting ◽

J. L. Morrison ◽

G. S. Posterino

Keyword(s):

Right Ventricular ◽

Papillary Muscle ◽

Late Gestation ◽

Postnatal Life ◽

Excitation Contraction Coupling ◽

Contraction Coupling ◽

Force Development ◽

Uptake Rates ◽

Significant Difference ◽

The Right

The force-generating capacity of cardiomyocytes rapidly changes during gestation and early postnatal life coinciding with a transition in cardiomyocyte nucleation in both mice and rats. Changes in nucleation, in turn, appear to coincide with important changes in the excitation-contraction coupling architecture. However, it is not clear whether similar changes are observed in other mammals in which this transition occurs prenatally, such as sheep. Using small (70–300 μM diameter) chemically skinned cardiomyocyte bundles from the right ventricular papillary muscle of sheep fetuses at 126–132 and 137–140 days (d) gestational age (GA), we aimed to examine whether changes in cardiomyocyte nucleation during late gestation coincided with developmental changes in excitation-contraction coupling parameters (e.g., Ca2+ uptake, Ca2+ release, and force development). All experiments were conducted at room temperature (23 ± 1°C). We found that the proportion of mononucleate cardiomyocytes decreased significantly with GA (126–132d, 45.7 ± 4.7%, n = 7; 137–140d, 32.8 ± 1.6%, n = 6; P < 0.05). When we then examined force development between the two groups, there was no significant difference in either the maximal Ca2+-activated force (6.73 ± 1.54 mN/mm2, n = 14 vs. 6.55 ± 1.25 mN/mm2, n = 7, respectively) or the Ca2+ sensitivity of the contractile apparatus (pCa at 50% maximum Ca2+-activated force: 126–132d, 6.17 ± 0.06, n = 14; 137–140d, 6.24 ± 0.08, n = 7). However, sarcoplasmic reticulum (SR) Ca2+ uptake rates (but not Ca2+ release) increased with GA ( P < 0.05). These data reveal that during late gestation in sheep when there is a major transition in cardiomyocyte nucleation, SR Ca2+ uptake rates increase, which would influence total SR Ca2+ content and force production.

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