Molecular basis of depression of Ca2+ sensitivity of tension by acid pH in cardiac muscles of the mouse and the rat

Ding, Xiaoling; Akella, Arvind B.; Sonnenblick, Edmund H.; Rao, Venu G.; Gulati, Jagdish

doi:10.1016/s1071-9164(96)80019-4

Cited by 6 publications

(4 citation statements)

References 34 publications

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“…The molecular mechanism for the pH‐induced reduction in Ca 2+ sensitivity is not known, but one possibility is that the excess H + ions compete with Ca 2+ and reduce their binding to the Ca 2+ binding sites on troponin C (TnC) (Ball et al 1994). Additionally, there may be changes in interactions between TnC and the other regulatory proteins (troponin I, troponin T and tropomyosin) and/or to altered binding of the troponin complex to the actin filament (Ball et al 1994; Ding et al 1996). The precise molecular interactions disrupted by reductions in pH i in skeletal muscle are not currently known.…”

Section: Discussionmentioning

confidence: 99%

The contribution of pH‐dependent mechanisms to fatigue at different intensities in mammalian single muscle fibres

Chin

Allen

1998

The Journal of Physiology

104

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The contribution of intracellular pH (pHi) to the failure of Ca2+ release and inhibition of contractile proteins observed during fatigue was assessed in single intact mouse muscle fibres at 22 °C. Fatigue was induced by repeated tetani at intensities designed to induce different levels of intracellular acidosis. Force and either intracellular free Ca2+ concentration ([Ca2+]i; measured using indo‐1) or pHi (measured using SNARF‐1) were recorded in fibres fatigued at two different intensities. Intensity was varied by the repetition rate of tetani and quantified by the duty cycle (the fraction of time when the muscle was tetanized). Stimulation at the low intensity (duty cycle ∼0.1) reduced force to 30 % of initial values in 206 ± 21 s (60 ± 7 tetani); at the high intensity (duty cycle ∼0.3) force was reduced to 30 % in 42 ± 7 s (43 ± 7 tetani) (P < 0.05; n= 14). When force was reduced to 30 % of initial values, tetanic [Ca2+]i had fallen from 648 ± 87 to 336 ± 64 nm (48 % decrease) at the low intensity but had only fallen from 722 ± 84 to 468 ± 60 nm (35 % decrease) at the higher intensity (P < 0.05 low vs. high intensity; n= 7). Fatigue resulted in reductions in Ca2+ sensitivity of the contractile proteins which were greater at the high intensity (pre‐fatigue [Ca2+]i required for 50 % of maximum force (Ca50) = 354 ± 23 nm; post‐fatigue Ca50= 421 ± 48 nm and 524 ± 43 nm for low and high intensities, respectively). Reductions in maximum Ca2+‐activated force (Fmax) were similar at the two intensities (pre‐fatigue Fmax= 328 ± 22 μN; post‐fatigue Fmax= 271 ± 20 and 265 ± 19 μN for low and high intensities, respectively). Resting pHi was 7.15 ± 0.05. During fatigue at the low intensity, pHi was reduced by 0.12 ± 0.02 pH units and at the high intensity pHi was reduced by 0.34 ± 0.07 pH units (P < 0.05; n= 5). Our results indicate that the more rapid fall in force at a high intensity is due to a reduction in Ca2+ sensitivity of the contractile proteins, probably related to the greater acidosis. Our data also indicate that the failure of Ca2+ release and reduced maximum Ca2+‐activated force observed during fatigue are not due to reductions in intracellular pH.

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Section: Discussionmentioning

confidence: 99%

The contribution of pH‐dependent mechanisms to fatigue at different intensities in mammalian single muscle fibres

Chin

Allen

1998

The Journal of Physiology

104

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“…By contrast, in some smooth muscles, opposite pH effects on maximum tension were observed (Spurway and Wray, 1987;Smith et al, 1998). For cardiac muscle and smooth muscle, troponin C (Ding et al, 1996) and tropomyosin (Yamaguchi et al, 1984), respectively, were considered as pH sensors, which influence actin-myosin interaction.…”

Section: Atp Step Experimentsmentioning

confidence: 99%

Effect of pH on the rate of myosin head detachment in molluscan catch muscle: are myosin heads involved in the catch state?

Höpflinger

Andruchova

Andruchov

et al. 2006

Journal of Experimental Biology

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Moderate alkalisation is known to terminate the catch state of bivalve mollusc smooth muscles such as the anterior byssus retractor muscle (ABRM) of Mytilus edulis L. In the present study, we investigated the effect of moderate alkalisation (pH 7.2-7.7 vs control pH 6.7) on the myosin head detachment rate in saponin-skinned fibre bundles of ABRM in order to investigate the possible role of myosin heads in the force maintenance during catch. The detachment rate of myosin heads was deduced from two types of experiments. (1) In stretch experiments on maximally Ca 2+ -activated fibre bundles (pCa 4.5), the rate of force decay after stepwise stretch was assessed. (2) In ATP step experiments, the rate of force decay from high force rigor (pCa>8) was evaluated. The ATP step was induced by photolysis of caged ATP. We found that moderate alkalisation induces relaxation of skinned fibres in catch, thereby reducing both force and stiffness, whereas it does not accelerate the rate of myosin head detachment. This acceleration, however, would be expected if catch would be simply due to myosin heads remaining sustainably attached to actin filaments. Thus, the myosin heads may be less involved in catch than generally assumed. Catch may possibly depend on a different kind of myofilament interconnections, which are abolished by moderate alkalisation.

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“…Calcium increases the TnI-TnC interaction, causing these subunits to act as a dynamic switch within the myofilament during systole and diastole. Acidosis diminishes myofilament Ca 2ϩ sensitivity, due in part to reduced Ca 2ϩ binding to troponin C (6,18), and impaired interactions between TnI and TnC during systole. Thus, this complex serves as a key regulator of beat-to-beat contractility in the heart (19).…”

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confidence: 99%

Single histidine button in cardiac troponin I sustains heart performance in response to severe hypercapnic respiratory acidosis in vivo

2009

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Intracellular acidosis is a profound negative regulator of myocardial performance. We hypothesized that titrating myofilament calcium sensitivity by a single histidine substituted cardiac troponin I (A164H) would protect the whole animal physiological response to acidosis in vivo. To experimentally induce severe hypercapnic acidosis, mice were exposed to a 40% CO(2) challenge. By echocardiography, it was found that systolic function and ventricular geometry were maintained in cTnI A164H transgenic (Tg) mice. By contrast, non-Tg (Ntg) littermates experienced rapid and marked cardiac decompensation during this same challenge. For detailed hemodymanic assessment, Millar pressure-conductance catheterization was performed while animals were treated with a beta-blocker, esmolol, during a severe hypercapnic acidosis challenge. Survival and load-independent measures of contractility were significantly greater in Tg vs. Ntg mice. This assay showed that Ntg mice had 100% mortality within 5 min of acidosis. By contrast, systolic and diastolic function were protected in Tg mice during acidosis, and they had 100% survival. This study shows that, independent of any beta-adrenergic compensation, myofilament-based molecular manipulation of inotropy by histidine-modified troponin I maintains cardiac inotropic and lusitropic performance and markedly improves survival during severe acidosis in vivo.

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Molecular basis of depression of Ca2+ sensitivity of tension by acid pH in cardiac muscles of the mouse and the rat

Cited by 6 publications

References 34 publications

The contribution of pH‐dependent mechanisms to fatigue at different intensities in mammalian single muscle fibres

The contribution of pH‐dependent mechanisms to fatigue at different intensities in mammalian single muscle fibres

Effect of pH on the rate of myosin head detachment in molluscan catch muscle: are myosin heads involved in the catch state?

Single histidine button in cardiac troponin I sustains heart performance in response to severe hypercapnic respiratory acidosis in vivo

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