Length Dependence of Cardiac Myofilament Ca2+ Sensitivity in the Presence of Substitute Nucleoside Triphosphates

Smith, Stephen H.; Fuchs, Franklin

doi:10.1006/jmcc.2002.1537

Cited by 6 publications

(5 citation statements)

References 32 publications

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“…Although we (5-8) and others (9)(10)(11)(12)(13)(14)(15)(16)(17) have characterized the effect of dATP on striated (skeletal and cardiac) muscle, its effect on smooth muscle is unknown. To determine whether vascular smooth muscle responds differently than striated muscle, we measured contraction of nontransgenic mouse aortic muscle strips with complete replacement of ATP for dATP.…”

Section: S2bmentioning

confidence: 99%

“…We (5)(6)(7)(8) and others (9)(10)(11)(12)(13)(14)(15)(16)(17) have reported that striated muscle myosin can use most naturally occurring nucleotides to support cross-bridge cycling and contraction to varying degrees. Although most are not as effective as ATP, we found that 2-deoxy-ATP (dATP) is more effective than ATP as a substrate for contraction of demembranated cardiac muscle, augmenting both force and shortening at all levels of Ca 2+ -mediated contractile activation (5)(6)(7)(8).…”

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confidence: 99%

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Transgenic overexpression of ribonucleotide reductase improves cardiac performance

Nowakowski

Kolwicz

Korte

et al. 2013

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

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We previously demonstrated that cardiac myosin can use 2-deoxy-ATP (dATP) as an energy substrate, that it enhances contraction and relaxation with minimal effect on calcium-handling properties in vitro, and that contractile enhancement occurs with only minor elevation of cellular [dATP]. Here, we report the effect of chronically enhanced dATP concentration on cardiac function using a transgenic mouse that overexpresses the enzyme ribonucleotide reductase (TgRR), which catalyzes the rate-limiting step in de novo deoxyribonucleotide biosynthesis. Hearts from TgRR mice had elevated left ventricular systolic function compared with wild-type (WT) mice, both in vivo and in vitro, without signs of hypertrophy or altered diastolic function. Isolated cardiomyocytes from TgRR mice had enhanced contraction and relaxation, with no change in Ca 2+ transients, suggesting targeted improvement of myofilament function. TgRR hearts had normal ATP and only slightly decreased phosphocreatine levels by 31 P NMR spectroscopy, and they maintained rate responsiveness to dobutamine challenge. These data demonstrate long-term (at least 5-mo) elevation of cardiac [dATP] results in sustained elevation of basal left ventricular performance, with maintained β-adrenergic responsiveness and energetic reserves. Combined with results from previous studies, we conclude that this occurs primarily via enhanced myofilament activation and contraction, with similar or faster ability to relax. The data are sufficiently compelling to consider elevated cardiac [dATP] as a therapeutic option to treat systolic dysfunction.metabolism | inotropy | cross-bridge cycling A wide variety of cardiac pathologies such as myocardial infarct, dilated cardiomyopathy, and congestive heart failure involve reduced systolic function of ventricles that often results from altered ATP-mediated actin-myosin (cross-bridge) cycling (1-4). The schematic shown in Fig. 1 outlines the basic components of this chemomechanical cycle that are critical to understand how cardiomyocytes use energy to develop tension and shortening: (i) ATP bound to detached myosin is hydrolyzed to ADP and inorganic phosphate (Pi); (ii) myosin binds to actin and undergoes the power-stroke associated with Pi release, tension development, and shortening; (iii) ADP is released from myosin; and (iv) ATP binds and precipitates myosin detachment from actin.We (5-8) and others (9-17) have reported that striated muscle myosin can use most naturally occurring nucleotides to support cross-bridge cycling and contraction to varying degrees. Although most are not as effective as ATP, we found that 2-deoxy-ATP (dATP) is more effective than ATP as a substrate for contraction of demembranated cardiac muscle, augmenting both force and shortening at all levels of Ca 2+ -mediated contractile activation (5-8). Our detailed biochemical and mechanical analysis suggests that dATP increases the rates of both myosin binding and product release (steps 2 and 3 in Fig. 1) (6). More recently, we reported that adenoviral overexpres...

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Section: S2bmentioning

confidence: 99%

mentioning

confidence: 99%

Transgenic overexpression of ribonucleotide reductase improves cardiac performance

Nowakowski

Kolwicz

Korte

et al. 2013

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

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“…There is significant evidence that the steep enhancement of force with increasing sarcomere length in cardiac muscle results from increased cross-bridge proximity to thin filament binding sites (33,34), although there is evidence that lattice spacing may not be the only factor (4). It should be noted that the steep length dependence of force is maintained only at higher temperatures, whereas lowering temperature eliminates the effects of sarcomere length on force at all activating [Ca 21 ] (24).…”

Section: Implications For Understanding Cardiac Function-the Frank-stmentioning

confidence: 99%

“…It should be noted that the steep length dependence of force is maintained only at higher temperatures, whereas lowering temperature eliminates the effects of sarcomere length on force at all activating [Ca 21 ] (24). The recent suggestions that crossbridge affinity for actin in the weak-binding states (M.ATP and M.ADP.P i ) is modulated by lattice spacing offers a potential explanation for the strong temperature dependence of length-dependent activation (6,33,34). At low temperature, where the M.ATP state is favored, a significant fraction of the cross-bridges, with their flexible structures, may have ready access to binding sites on the thin filament.…”

Section: Implications For Understanding Cardiac Function-the Frank-stmentioning

confidence: 99%

X-ray Diffraction Studies of the Thick Filament in Permeabilized Myocardium from Rabbit

Martyn

Zaman

et al. 2006

Biophysical Journal

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Low angle x-ray diffraction patterns from relaxed permeabilized rabbit cardiac trabeculae and psoas muscle fibers were compared. Temperature was varied from 25 degrees C to 5 degrees C at 200 mM and 50 mM ionic strengths (mu), respectively. Effects of temperature and mu on the intensities of the myosin layer lines (MLL), the equatorial intensity ratio I(1,1)/I(1,0), and the spacing of the filament lattice are similar in both muscles. At 25 degrees C, particularly at mu = 50 mM, the x-ray patterns exhibited up to six orders of MLL and sharp meridional reflections, signifying that myosin heads (cross-bridges) are distributed in a well-ordered helical array. Decreasing temperature reduced MLL intensities but increased I(1,1)/I(1,0). Decreases in the MLL intensities indicate increasing disorder in the distribution of cross-bridges on the thick filaments surface. In the skeletal muscle, order/disorder is directly correlated with the hydrolysis equilibrium of ATP by myosin, [M.ADP.P(i)]/[M.ATP]. Similar effects of temperature on MLL and similar biochemical ATP hydrolysis pathway found in both types of muscles suggest that the order/disorder states of cardiac cross-bridges may well be correlated with the same biochemical and structural states. This implies that in relaxed cardiac muscle under physiological conditions, the unattached cross-bridges are largely in the M.ADP.P(i) state and with the lowering of the temperature, the equilibrium is increasingly in favor of [M.ATP] and [A.M.ATP]. There appear to be some differences in the diffraction patterns from the two muscles, however. Mainly, in the cardiac muscle, the MLL are weaker, the I(1,1)/I(1,0) ratio tends to be higher, and the lattice spacing D(10), larger. These differences are consistent with the idea that under a wide range of conditions, a greater fraction of cross-bridges is weakly bound to actin in the myocardium.

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“…It has been demonstrated many times that an increase in the diastolic or relaxed SL induces a decrease in the spacing between the filaments within the lattice (4,7,17,18,21,24,26); for a thorough review of factors affecting lattice spacing, see Millman (32). With a decreasing myofilament lattice spacing, the probability of forming strong binding cross bridges might be expected to increase, thereby increasing the amount of force production for the same amount of activating calcium (7,16,31,40). This hypothesis was further supported by experiments by Fitzsimons and Moss (14) where they demonstrated that the introduction of nonforce-generating strong binding cross bridges (NEM-S1) was able to shift the calcium sensitivity of cardiac myocytes at short SLs (1.90 m) to that of myocytes at long SLs (2.25 m).…”

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confidence: 99%

Myosin head orientation: a structural determinant for the Frank-Starling relationship

Farman

Gore

Allen

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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The cellular mechanism underlying the Frank-Starling law of the heart is myofilament length-dependent activation. The mechanism(s) whereby sarcomeres detect changes in length and translate this into increased sensitivity to activating calcium has been elusive. Small-angle X-ray diffraction studies have revealed that the intact myofilament lattice undergoes numerous structural changes upon an increase in sarcomere length (SL): lattice spacing and the I(1,1)/I(1,0) intensity ratio decreases, whereas the M3 meridional reflection intensity (I(M3)) increases, concomitant with increases in diastolic and systolic force. Using a short (∼10 ms) X-ray exposure just before electrical stimulation, we were able to obtain detailed structural information regarding the effects of external osmotic compression (with mannitol) and obtain SL on thin intact electrically stimulated isolated rat right ventricular trabeculae. We show that over the same incremental increases in SL, the relative changes in systolic force track more closely to the relative changes in myosin head orientation (as reported by I(M3)) than to the relative changes in lattice spacing. We conclude that myosin head orientation before activation determines myocardial sarcomere activation levels and that this may be the dominant mechanism for length-dependent activation.

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Length Dependence of Cardiac Myofilament Ca2+ Sensitivity in the Presence of Substitute Nucleoside Triphosphates

Cited by 6 publications

References 32 publications

Transgenic overexpression of ribonucleotide reductase improves cardiac performance

Transgenic overexpression of ribonucleotide reductase improves cardiac performance

X-ray Diffraction Studies of the Thick Filament in Permeabilized Myocardium from Rabbit

Myosin head orientation: a structural determinant for the Frank-Starling relationship

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