Depressed Frank–Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation ΔK210

Inoue, Takahiro; Kobirumaki-Shimozawa, Fuyu; Kagemoto, Tatsuya; Fujii, Teruyuki; Terui, Takako; Kusakari, Yoichiro; Hongo, Kazuhiro; Morimoto, Sachio; Ohtsuki, Iwao; Hara, Kazuhiro; Fukuda, Norio

doi:10.1016/j.yjmcc.2013.07.001

Cited by 26 publications

(57 citation statements)

References 43 publications

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“…The notion that the mutant Tn may exert a modulatory role on MHC-dependent function also comes from the study of Midde et al (31), which shows that cardiomyopathy-related mutations in TnT alter the disposition of XBs. Other studies also suggest that the DCMrelated mutations in human TnT (R141W, R131W, and ⌬K210) alter XB cycling kinetics, without affecting the maximal tension generating ability of the cardiac muscle (21,32,50). These observations, including a diverse set of data from our current study, strongly support the notion that TnT R144W alters thin filament-based allosteric mechanisms.…”

Section: Discussionsupporting

confidence: 86%

The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by α- and β-myosin heavy chain isoforms

Gollapudi

Tardiff

Chandra

2015

American Journal of Physiology-Heart and Circulatory Physiology

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Given the differential impact of α- and β-myosin heavy chain (MHC) isoforms on how troponin T (TnT) modulates contractile dynamics, we hypothesized that the effects of dilated cardiomyopathy (DCM) mutations in TnT would be altered differently by α- and β-MHC. We characterized dynamic contractile features of normal (α-MHC) and transgenic (β-MHC) mouse cardiac muscle fibers reconstituted with a mouse TnT analog (TnTR144W) of the human DCM R141W mutation. TnTR144W did not alter maximal tension but attenuated myofilament Ca(2+) sensitivity (pCa50) to a similar extent in α- and β-MHC fibers. TnTR144W attenuated the speed of cross-bridge (XB) distortion dynamics (c) by 24% and the speed of XB recruitment dynamics (b) by 17% in α-MHC fibers; however, both b and c remained unaltered in β-MHC fibers. Likewise, TnTR144W attenuated the rates of XB detachment (g) and tension redevelopment (ktr) only in α-MHC fibers. TnTR144W also decreased the impact of strained XBs on the recruitment of new XBs (γ) by 30% only in α-MHC fibers. Because c, b, g, ktr, and γ are strongly influenced by thin filament-based cooperative mechanisms, we conclude that the TnTR144W- and β-MHC-mediated changes in the thin filament interact to produce a less severe functional phenotype, compared with that brought about by TnTR144W and α-MHC. These observations provide a basis for lower mortality rates of humans (β-MHC) harboring the TnTR141W mutant compared with transgenic mouse studies. Our findings strongly suggest that some caution is necessary when extrapolating data from transgenic mouse studies to human hearts.

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Section: Discussionsupporting

confidence: 86%

The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by α- and β-myosin heavy chain isoforms

Gollapudi

Tardiff

Chandra

2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Likewise, these values are in good agreement with those obtained by others [14] in epicardial myocytes in the LV of Langendorff perfused isolated mouse heart. Therefore, the present finding may strengthen the rationale for the use of the T-tubular distance as SL with membrane-staining reagents such as CellMask ([6, 8] and the present study) or di-4-ANNEPS [10, 11] in the isolated heart or the heart in vivo . However, di-4-ANNEPS reportedly slows the heart's conduction velocity and possibly affects subsequent mechanical properties [15].…”

Section: Discussionsupporting

confidence: 75%

“…As in our previous studies [6, 8], SL or the T-tubular distance was measured by analyzing the fluorescence plot profiles along the longitudinal axis of a myocyte (or myocytes) by using the ImageJ software (National Institutes of Health, Bethesda, MD, USA) [the region of interest (ROI) width, 5 pixels]. Briefly, the profiles were analyzed using the multipeak Gaussian fitting with a linear function of offset ( Y = a X + b), based on the Levenberg-Marquardt algorithm, and SL or the T-tubular distance was calculated as the distance between the centers of two adjacent peaks (see [1] for details).…”

Section: Methodsmentioning

confidence: 66%

“…Previously we labeled the T-tubules of cardiomyocytes by perfusing the isolated heart via the aorta with Tyrode's solution containing CellMask (1 μ M), and determined the T-tubular distance at rest (i.e., ~2.0 μ m; [8]). In the present study, we investigated whether or not the heart's T-tubular system can be stained by using CellMask in vivo .…”

Section: Resultsmentioning

confidence: 99%

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Optimization of Fluorescent Labeling for In Vivo Nanoimaging of Sarcomeres in the Mouse Heart

Kobirumaki-Shimozawa

Togo

Oyama

et al. 2018

BioMed Research International

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The present study was conducted to systematically investigate the optimal viral titer as well as the volume of the adenovirus vector (ADV) that expresses α-actinin-AcGFP in the Z-disks of myocytes in the left ventricle (LV) of mice. An injection of 10 μL ADV at viral titers of 2 to 4 × 1011 viral particles per mL (VP/mL) into the LV epicardial surface consistently expressed α-actinin-AcGFP in myocytes in vivo, with the fraction of AcGFP-expressing myocytes at ~10%. Our analysis revealed that SL was ~1.90-2.15 μm upon heart arrest via deep anesthesia. Likewise, we developed a novel fluorescence labeling method of the T-tubular system by treating the LV surface with CellMask Orange (CellMask). We found that the T-tubular distance was ~2.10-2.25 μm, similar to SL, in the healthy heart in vivo. Therefore, the present high-precision visualization method for the Z-disks or the T-tubules is beneficial to unveiling the mechanisms of myocyte contraction in health and disease in vivo.

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“…All solutions used in the present study contained protease inhibitors (0.5 mmol/L PMSF, 0.04 mmol/L leupeptin, and 0.01 mmol/L E64) to avoid protein degradations. [34][35][36][37] A myofibril suspension in relaxing solution was placed in an experimental chamber, which was made of a pair of coverslips (Matsunami Glass Ind, Osaka, Japan) and a Teflon block, under the phase-contrast microscope (TE2000, Nikon Corp, Tokyo, Japan; Figure 1C). For the analyses of Ca-SPOC, a single myofibril (or a bundle composed of 2 myofibrils) floating in the chamber was held by twining its ends around a pair of stiff glass microneedles with the micromanipulators (MHW-3, Narishige Inc, Tokyo, Japan).…”

Section: Myofibrilsmentioning

confidence: 99%

Sarcomeric Auto-Oscillations in Single Myofibrils From the Heart of Patients With Dilated Cardiomyopathy

Kagemoto

Oyama

Yamane

et al. 2018

Circ: Heart Failure

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Background: Left ventricular wall motion is depressed in patients with dilated cardiomyopathy (DCM). However, whether or not the depressed left ventricular wall motion is caused by impairment of sarcomere dynamics remains to be fully clarified. Methods and Results: We analyzed the mechanical properties of single sarcomere dynamics during sarcomeric auto-oscillations (calcium spontaneous oscillatory contractions [Ca-SPOC]) that occurred at partial activation under the isometric condition in myofibrils from donor hearts and from patients with severe DCM (New York Heart Association classification III-IV). Ca-SPOC reproducibly occurred in the presence of 1 μmol/L free Ca 2+ in both nonfailing and DCM myofibrils, and sarcomeres exhibited a saw-tooth waveform along single myofibrils composed of quick lengthening and slow shortening. The period of Ca-SPOC was longer in DCM myofibrils than in nonfailing myofibrils, in association with prolonged shortening time. Lengthening time was similar in both groups. Then, we performed Tn (troponin) exchange in myofibrils with a DCM-causing homozygous mutation (K36Q) in cTnI (cardiac TnI). On exchange with the Tn complex from healthy porcine ventricles, period, shortening time, and shortening velocity in cTnI-K36Q myofibrils became similar to those in Tn-reconstituted nonfailing myofibrils. Protein kinase A abbreviated period in both Tn-reconstituted nonfailing and cTnI-K36Q myofibrils, demonstrating acceleration of cross-bridge kinetics. Conclusions: Sarcomere dynamics was found to be depressed under loaded conditions in DCM myofibrils because of impairment of thick-thin filament sliding. Thus, microscopic analysis of Ca-SPOC in human cardiac myofibrils is beneficial to systematically unveil the kinetic properties of single sarcomeres in various types of heart disease.

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Depressed Frank–Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation ΔK210

Cited by 26 publications

References 43 publications

The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by α- and β-myosin heavy chain isoforms

The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by α- and β-myosin heavy chain isoforms

Optimization of Fluorescent Labeling for In Vivo Nanoimaging of Sarcomeres in the Mouse Heart

Sarcomeric Auto-Oscillations in Single Myofibrils From the Heart of Patients With Dilated Cardiomyopathy

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