Acidosis in cardiac muscle is associated with a decrease in developed force. We hypothesized that slow skeletal troponin I (ssTnI), which is expressed in neonatal hearts, is responsible for the observed decreased response to acidic conditions. To test this hypothesis directly, we used adult transgenic (TG) mice that express ssTnI in the heart. Cardiac TnI (cTnI) was completely replaced by ssTnI either with a FLAG epitope introduced into the N‐terminus (TG‐ssTnI*) or without the epitope (TG‐ssTnI) in these mice. TG mice that express cTnI were also generated as a control TG line (TG‐cTnI). Non‐transgenic (NTG) littermates were used as controls. We measured the force‐calcium relationship in all four groups at pH 7.0 and pH 6.5 in detergent‐extracted fibre bundles prepared from left ventricular papillary muscles. The force‐calcium relationship was identical in fibre bundles from NTG and TG‐cTnI mouse hearts, therefore NTG mice served as controls for TG‐ssTnI* and TG‐ssTnI mice. Compared to NTG controls, the force generated by fibre bundles from TG mice expressing ssTnI was more sensitive to Ca2+. The shift in EC50 (the concentration of Ca2+ at which half‐maximal force is generated) caused by acidic pH was significantly smaller in fibre bundles isolated from TG hearts compared to those from NTG hearts. However, there was no difference in the force‐calcium relationship between hearts from the TG‐ssTnI* and TG‐ssTnI groups. We also isolated papillary muscles from the right ventricle of NTG and TG mouse hearts expressing ssTnI and measured isometric force at extracellular pH 7.33 and pH 6.75. At acidic pH, after an initial decline, twitch force recovered to 60 ± 3 % (n= 7) in NTG papillary muscles, 98 ± 2 % (n= 5) in muscles from TG‐ssTnI* and 96 ± 3 % (n= 7) in muscles from TG‐ssTnI hearts. Our results indicate that TnI isoform composition plays a crucial role in the determination of myocardial force sensitivity to acidosis.
The cellular mechanisms underlying the development of congestive heart failure (HF) are not well understood. Accordingly, we studied myocardial function in isolated right ventricular trabeculae from rats in which HF was induced by left ventricular myocardial infarction (MI). Both early-stage (12 wk post-MI; E-pMI) and late, end-stage HF (28 wk post-Mi; L-pMI) were studied. HF was associated with decreased sarcoplasmic reticulum Ca2+ ATPase protein levels (28% E-pMI; 52% L-pMI). HF affected neither sodium/calcium exchange, ryanodine receptor, nor phospholamban protein levels. Twitch force at saturating extracellular [Ca2+] was depressed in HF (30% E-pMI; 38% L-pMI), concomitant with a marked increase in sensitivity of twitch force toward extracellular [Ca2+] (26% E-pMI; 68% L-pMI). Ca2+-saturated myofilament force development in skinned trabeculae was unchanged in E-pMI but significantly depressed in L-pMI (45%). Tension-dependent ATP hydrolysis rate was depressed in L-pMI (49%), but not in E-pMI. Our results suggest a hierarchy of cellular events during the development of HF, starting with altered calcium homeostasis during the early phase followed by myofilament dysfunction at end-stage HF.
Applying external mechanical vibration during the relaxation phase of rat papillary muscle decreases the duration of the first part of the relaxation phase. To elucidate the basic mechanism responsible for this shortening of the relaxation period, we applied a controlled vibration to isolated twitching rat papillary muscles during various phases in the relaxation of a twitch. The first part of the relaxation phase was accelerated when length perturbations were applied in the first part of the relaxation of a twitch, dependent on both amplitude and frequency of the perturbation. When vibrations were applied in the first half of the relaxation, the second phase of relaxation was slightly slower (about 20%), but when no vibrations were applied in the first phase, relaxation could be accelerated by applying vibration in the latter half of the relaxation phase. Thus, in the latter half of relaxation, the acceleration of relaxation depended upon perturbation events earlier during that twitch. This study indicates that vibration-induced acceleration of relaxation is due (at least in part) to an apparent increase in detachment rate of attached cross-bridges from the thin filament without substantial reattachment.
We examined whether the three states model can explain the systolic and relaxation properties of cardiac muscle to clarify what factors affect these properties. Changing the values of the parameters describing the calcium transient and calcium sensitivity, we estimated the effects of these parameters on the systolic and relaxation properties of twitch contraction. The simulations showed the following four features: 1) An increase in the maximum calcium concentration and calcium sensitivity, and a prolongation of the calcium transient led to an increase in peak tension associated with an increase in the time to peak tension. 2) An increase in myosin ATPase activity led to an increase in peak tension associated with a decrease in the time to peak tension. 3) An increase of peak tension was accompanied by a prolongation of the late systolic period. 4) The constant of the late tension relaxation from 25% to 10% of the peak tension was altered when the crossbridge cycling rate, the resting calcium concentration or the late decline of the calcium transient was changed. The simulation were not contradictory to the experimental results and showed that three state muscle model can provide qualitative descriptions on the systolic and relaxation characteristics of cardiac muscle.
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