Regulation of human heart contractility by essential myosin light chain isoforms.

Morano, Marija; Zacharzowski, Udo; Maier, Michaela; Lange, Peter; Alexi-Meskishvili, Vladimir; Haase, Hannelore; Morano, Ingo

doi:10.1172/jci118813

Cited by 125 publications

(115 citation statements)

References 40 publications

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“…Changes in crossbridge cycling also have been observed with altered light chains in myosin in vitro motility assays as well as in fiber studies of unloaded velocity with substituted light chains (12,(18)(19)(20). The increased unloaded velocity is presumably attributable to a strain-dependent increased rate of crossbridge detachment.…”

mentioning

confidence: 85%

The stretch-activation response may be critical to the proper functioning of the mammalian heart

Vemuri

Lankford

Poetter

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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The "stretch-activation" response is essential to the generation of the oscillatory power required for the beating of insect wings. It has been conjectured but not previously shown that a stretch-activation response contributes to the performance of a beating heart. Here, we generated transgenic mice that express a human mutant myosin essential light chain derived from a family with an inherited cardiac hypertrophy. These mice faithfully replicate the cardiac disease of the patients with this mutant allele. They provide the opportunity to study the stretch-activation response before the hearts are distorted by the hypertrophic process. Studies disclose a mismatch between the physiologic heart rate and resonant frequency of the cardiac papillary muscles expressing the mutant essential light chain. This discordance reduces oscillatory power at frequencies that correspond to physiologic heart-rates and is followed by subsequent hypertrophy. It appears, therefore, that the stretchactivation response, first described in insect flight muscle, may play a role in the mammalian heart, and its further study may suggest a new way to modulate human cardiac function.The human heart is a prodigious organ that beats Ϸ3 billion times during a 70-year lifetime. It is powered by the cardiac isoform of the myosin molecule, a molecular motor that transduces chemical energy released by its ATPase activity into directed movement. This myosin molecule has a globular head tapering to a slender neck to which two myosin light chains are bound. The neck is connected to a rod-like tail that is responsible for the self assembly of myosin molecules into thick filaments. In striated muscle, actin-containing thin filaments are moved past interdigitating thick filaments by myosin heads, which extend from the thick filaments and asynchronously deliver repetitive impulses to actin (1-3). The interdigitating filaments are arranged in a quasicrystalline lattice geometry that influences the strain between actin and myosin molecules in the fiber. Because individual myosin heads are constrained by this lattice organization, a series elastic element must store mechanical energy to accommodate the asynchronous crossbridge action. Variations in myosin isoforms, associated proteins, and lattice spacing introduce diversity in actomyosin interaction and power output of the muscle fiber (4, 5).Insect flight muscle (IFM) has evolved to accentuate and exploit a property that is of unknown physiologic significance in other types of muscle fibers. The wing beat frequency of the common fly is Ϸ150 beats͞s. It would be energetically very costly to repetitively pump calcium ions across the sarcoplasmic membrane at this rate. Instead, an exaggerated stretch-activated response (active in the presence of a constantly elevated calcium level) generates oscillatory power output in IFM. This stretchactivation response was first described in Pringle's studies of IFM in 1949 (6). More recently, Kawai refers to it as "process B" and routinely observes it in sinusoida...

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mentioning

confidence: 85%

The stretch-activation response may be critical to the proper functioning of the mammalian heart

Vemuri

Lankford

Poetter

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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“…It appears that these changes are potentially reversible because surgical intervention with subsequent normalization of the hemodynamic state decreases ALC 1 expression (20). The functional role of ALC 1 appears to lie in increasing the cycling kinetics of cardiac cross-bridges, thus regulating the contractile state of the heart (21,22). Because ALC 1 is the fast contracting isoform and improves contractility, its re-expression in myocardium is most probably considered to be a part of the adaptive response during cardiac hypertrophy (23).…”

Section: Myofibrillar Assembly In Cardiac Hypertrophymentioning

confidence: 99%

“…Although ALC 1 becomes re-expressed in the overloaded human ventricle (17,19,20,22,74), β-MHC may combine with either ALC 1 and/or ventricular light chain 1 (VLC 1 ) to form two homodimers and one heterodimer in diseased human ventricles (23). The main consequence of ALC 1 re-expression in the ventricle is the increase of Ca 2+ sensitivity of the contractile apparatus (74).…”

Section: Myofibrillar Assembly In Congestive Hfmentioning

confidence: 99%

“…In this way, ALC 1 modulates ventricular contractility by increasing the cross-bridge kinetics of the β-MHC isoform. β-MHC, in combination with ALC 1 , becomes a faster isoform and at the same time, it improves the efficiency of cardiac contraction (22). The presence of ALC 1 can be seen as an advantage even in HF because it allows for a faster and larger force development at the decreased systolic Ca 2+ levels under higher heart rate conditions (75).…”

Section: Myofibrillar Assembly In Congestive Hfmentioning

confidence: 99%

“…On the other hand, the expression of ALC 2 was not detected in normal developing (76) or diseased human ventricles (19,20). Nevertheless, it is now well established that in rodent ventricles, there is an MHC isoform shift, rather than a change in MLC expression by hormonal, developmental or hemodynamic alterations, whereas in humans, changes in MLC isoforms (particularly ALC 1 ), and not those of MHC, seem to regulate ventricular contractility (Table 2) (22,74). It should be noted that the level of ALC 1 is much lower at the end stages of HF (New York Heart Association classes III to IV) than at the earlier stages (New York Heart Association classes I to II) (77).…”

Section: Myofibrillar Assembly In Congestive Hfmentioning

confidence: 99%

See 2 more Smart Citations

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

Macháčková¹,

Barta²,

Dhalla³

2006

Canadian Journal of Cardiology

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In vitro motility assay of atrial and ventricular myosin from pig

1997

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The role of myosin isoforms in determining contractile filament velocity in the atrium and ventricle of the pig heart was studied by measuring the motion of fluorescently labeled actin over myosin (in vitro motility assay). A rapid and relatively simple method for purification of myosin from small tissue samples was used. The relative extent of light chain-2 phosphorylation was about 30% in both atrial and ventricular myosin extracts. Although the extracted myosin was not free from contaminating proteins, mainly actin, the mean velocity at optimal pH and 32 degrees C of both atrial (3.3 microns/s) and ventricular (2.3 microns/s) myosin were similar to those obtained using extensively purified myosin. The filament sliding velocities using isolated myosin and actin are lower than those estimated from previously published experiments on skinned fiber preparations, which might reflect an influence on sliding velocity by the filament organization or regulatory proteins in the muscle fiber. However, the ratio between velocities of atrial and ventricular myosin was similar in the motility assay (1.5) and muscle fiber experiments (1.6), which might suggest that these two methods reflect the same fundamental processes in cardiac contraction and that the difference in filament sliding velocity between the atrium and ventricle of the pig heart is determined my their myosin isoforms.

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Regulation of human heart contractility by essential myosin light chain isoforms.

Cited by 125 publications

References 40 publications

The stretch-activation response may be critical to the proper functioning of the mammalian heart

The stretch-activation response may be critical to the proper functioning of the mammalian heart

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

In vitro motility assay of atrial and ventricular myosin from pig

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