Calcium cycling and contractile activation in intact mouse cardiac muscle

Gao, Wei Dong; Pérez, Néstor Gustavo; Marbán, Eduardo

doi:10.1111/j.1469-7793.1998.175bu.x

Cited by 112 publications

(119 citation statements)

References 33 publications

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“…In contrast, isolated rat myocardium demonstrates Ca 2ϩ overload much more readily. 1 Our observation that there was a prolongation of only after extreme afterload (124 to 172 mm Hg) is consistent with mice having faster Ca 2ϩ reuptake capability than larger mammals, such that much higher calcium transients would be needed to saturate the uptake mechanism.…”

Section: Discussionsupporting

confidence: 63%

“…It is known that murine cardiac muscle is less sensitive to calcium than muscle from larger mammalian species, with lower F max and higher Ca 50 . 1 In addition, the murine heart is resistant to calcium overload because of rapid reuptake of calcium by the sarcoplasmic reticulum, 1,2 and the force-frequency relation in the intact murine left ventricle (LV) is flat at physiological heart rates, 2 unlike the near doubling of contractility over a physiological range of heart rates in larger mammals. Finally, under physiological conditions, the murine heart has greater sympathetic stimulation and less vagal stimulation than do hearts of larger mammals.…”

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confidence: 99%

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Enhancement of Contractility With Sustained Afterload in the Intact Murine Heart

et al. 2003

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Background-It has been hypothesized that because of its rapid heart rate, the intact murine heart functions near maximal contractility in the basal state. If this hypothesis is correct, then the fast and slow components of myocardial length-dependent activation should be blunted compared with larger mammals. Methods and Results-Mice (nϭ24) were anesthetized, and via an open chest, LV pressure-volume relationships were determined by a dual-frequency conductance catheter system. Baseline pressure-volume relationships were determined during transient occlusion of the inferior vena cava, and repeat measurements were made after 1 (nϭ10) and 7 (nϭ21) minutes of sustained aortic occlusion. Control experiments were performed in a subset of mice (nϭ3

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Section: Discussionsupporting

confidence: 63%

mentioning

confidence: 99%

Enhancement of Contractility With Sustained Afterload in the Intact Murine Heart

et al. 2003

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“…An exploded view focused on the region of minimum amplitude (Fig. 5, C and D) shows the significant differences in f dip at pCa 5.75, near systolic levels of intracellular calcium measured in electrically stimulated, intact mouse myocardium (38). Differences in complex modulus characteristics at both maximum and submaximum calcium activation suggest that residues 5-14 of the ELC extension affect cross-bridge kinetics.…”

Section: Resultsmentioning

confidence: 99%

The Essential Light Chain N-terminal Extension Alters Force and Fiber Kinetics in Mouse Cardiac Muscle

Miller

Palmer

Ruch

et al. 2005

Journal of Biological Chemistry

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The functional significance of the actin-binding region at the N terminus of the cardiac myosin essential light chain (ELC) remains elusive. In a previous experiment, the endogenous ventricular ELC was replaced with a protein containing a 10-amino acid deletion at positions 5-14 (ELC1v⌬5-14, referred to as 1v⌬5-14), a region that interacts with actin (Sanbe, A., Gulick, J., Fewell, J., and Robbins, J. (2001) J. Biol. Chem. 276, 32682-32686). 1v⌬5-14 mice showed no discernable mutant phenotype in skinned ventricular strips. However, because the myofilament lattice swells upon skinning, the mutant phenotype may have been concealed by the inability of the ELC to reach the actin-binding site. Using the same mouse model, we repeated earlier measurements and performed additional experiments on skinned strips osmotically compressed to the intact lattice spacing as determined by x-ray diffraction. 1v⌬5-14 mice exhibited decreased maximum isometric tension without a change in calcium sensitivity. The decreased force was most evident in 5-6-month-old mice compared with 13-15-month-old mice and may account for the greater ventricular wall thickness in young 1v⌬5-14 mice compared with age-matched controls. No differences were observed in unloaded shortening velocity at maximum calcium activation. However, 1v⌬5-14 mice exhibited a significant difference in the frequency at which minimum complex modulus amplitude occurred, indicating a change in cross-bridge kinetics. We hypothesize that the ELC N-terminal extension interaction with actin inhibits the reversal of the power stroke, thereby increasing isometric force. Our results strongly suggest that an interaction between residues 5-14 of the ELC N terminus and the C-terminal residues of actin enhances cardiac performance.

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“…Several features of the activation curves are noteworthy. First, maximal Ca 2+ -activated force, or F max (48 ± 4.2 mN/mm 2 in wild-type, 45 ± 5.5 mN/mm 2 in mutant) is lower in both groups compared with muscles from younger mice of another strain (11). An overall comparison of the curves from mutant and wild-type mice reveals significant differences (P = 0.03 by multivariate ANOVA).…”

Section: Dynamics Of Twitches and Ca 2+ Transients In Wild-type And Mmentioning

confidence: 97%

“…The KH buffer was composed of (in mM): 142 Na + , 5 K + , 1. For the experiments to be technically successful, muscles must be long, thin, and nonbranching; such muscles are found only in ∼25% of mouse hearts (11). [Ca 2+ ] i was measured with fura-2 potassium salt introduced iontophoretically into one cell and allowed to spread throughout the muscle via gap junctions as described previously (12).…”

Section: Methodsmentioning

confidence: 99%

Altered cardiac excitation–contraction coupling in mutant mice with familial hypertrophic cardiomyopathy

Gao¹,

Pérez²,

Seidman³

et al. 1999

J. Clin. Invest.

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Familial hypertrophic cardiomyopathy (FHC) is an inherited autosomal dominant disease characterized by ventricular hypertrophy and myofibrillar disarray. Sudden cardiac death, especially among young athletes, represents the most severe outcome of FHC in affected individuals (1-3). The genetic alterations have been localized to genes that encode various myofibrillar proteins (4,5). Among these, the β-myosin heavy chain (β-MHC) gene was the first to be implicated and remains the most common identified cause of FHC. Recently, a transgenic model of FHC in mice with truncated troponin T (TnT) has also been developed (6). These transgenic mice hearts are smaller than wild-type, with fewer myocytes, but they exhibit significant delay in relaxation in response to increased work load with mild systolic dysfunction. Despite these advances, it is not yet clear how the genetic lesions produce the characteristic phenotype.Few studies have attempted to investigate the functional abnormalities of hypertrophic cardiac muscles of FHC. Lin et al. (7) showed increased motility of thin filaments containing mutant TnT (TnT I91N), a lesion associated with FHC. Similarly, myotubes with truncated TnT (also implicated in FHC) produced less force (8). Mutated myosin molecules also demonstrated decreased actin translocating activity (9). Nevertheless, direct evidence of altered function in intact myocardium is sparse, and little is known about the pathophysiology of excitation-contraction coupling in FHC.The recent introduction of an FHC mutation (Arg403Gln) into the mouse α-MHC gene has produced an animal model resembling, in many aspects, human FHC (10). Here, we have studied the physiological properties of muscles from the hearts of these mice. The results indicate that there are alterations in excitation-contraction coupling in mutant mice, with lesions in myofilament contraction and associated changes of intracellular Ca 2+ ([Ca 2+ ] i ) handling. MethodsMouse muscle preparation. Adult male mice (Black Swiss strain, ∼20 weeks old, ∼35 g; for a detailed description of the mouse model of FHC, see ref. 10) were anesthetized by intra-abdominal injection of sodium pentobarbital (∼10-20 mg), and the hearts were rapidly excised via midsternal thoracotomy. As described for wild-type mice of another strain (11), the hearts were retrogradely perfused with modified Krebs-Henseleit (KH) buffer with high K + (20 mM) and gassed with a 95% O 2 /5% CO 2 gas mixture in a dissection dish at room temperature. Trabeculae or small papillary muscles (in mm: wild-type 0.90 ± 0.34 long, 0.18 ± 0.08 wide, and 0.11 ± 0.05 thick, n = 8; mutant 0.70 ± 0.21 long, 0.21 ± 0.10 wide, and 0.12 ± 0.04 thick, n = 8; mean ± SD) were quickly dissected from the right ventricle and mounted between a force transducer and a micromanipulator in a perfusion bath. The muscles were superfused with KH buffer equilibrated with 95% O 2 /5% CO 2 . The KH buffer was composed of (in mM): 142 Na + , 5 K + , 1.2 Mg 2+ , 127.4 Cl -, 2 PO 4 -, 20 HCO 3 -, 1.0 CaCl 2 (pH 7.35-7.4). The ...

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Calcium cycling and contractile activation in intact mouse cardiac muscle

Cited by 112 publications

References 33 publications

Enhancement of Contractility With Sustained Afterload in the Intact Murine Heart

Enhancement of Contractility With Sustained Afterload in the Intact Murine Heart

The Essential Light Chain N-terminal Extension Alters Force and Fiber Kinetics in Mouse Cardiac Muscle

Altered cardiac excitation–contraction coupling in mutant mice with familial hypertrophic cardiomyopathy

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