Decrease in sarcoplasmic reticulum calcium content, not myofilament function, contributes to muscle twitch force decline in isolated cardiac trabeculae

Abstract

We set out to determine the factors responsible for twitch force decline in isolated intact rat cardiac trabeculae. The contractile force of trabeculae declined over extended periods of isometric twitch contractions. The force-frequency relationship within the frequency range of 4–8 Hz, at 37 °C, became more positive and the frequency optimum shifted to higher rates with this decline in baseline twitch tensions. The post-rest potentiation (37 °C), a phenomenon highly dependent on calcium handling mechanisms, became more pronounced with decrease in twitch tensions. We show that the main abnormality during muscle run-down was not due to a deficit in the myofilaments; maximal tension achieved using a K+ contracture protocol was either unaffected or only slightly decreased. Conversely, the sarcoplasmic reticulum (SR) calcium content, as assessed by rapid cooling contractures (from 27 °C to 0 °C), decreased, and had a close association with the declining twitch tensions (R2 ~ 0.76). SR Ca2+-ATPase, relative to Na+/Ca2+ exchanger activity, was not altered as there was no significant change in paired rapid cooling contracture ratios. Furthermore, confocal microscopy detected no abnormalities in the overall structure of the cardiomyocytes and t-tubules in the cardiac trabeculae (~23 °C). Overall, the data indicates that the primary mechanism responsible for force run-down in multi-cellular cardiac preparations is a decline in the SR calcium content and not the maximal tension generation capability of the myofilaments.

Insights into length-dependent regulation of cardiac cross-bridge cycling kinetics in human myocardium

“…Unlike in inbred animals, there is very substantial variability between human hearts due to multiple factors such as co-morbid disorders, life-style behaviors, medications, and genetics [35]. Therefore, the phosphorylation status in response to inhibitors needs to be compared within the same hearts.…”

“…It has been previously shown that this phenomenon is mainly, or even exclusively, due to muscle run-down of the preparation due to alterations in sarcoplasmic-reticulum calcium content [35] while the measured k tr remains stable throughout the course of the several experiments [7, 12, 35]. These previous studies suggest that the run-down that was observed in some of our experiments is not primarily due to the myofilament proteins and has minimal or no effect on our k tr measurements.…”

Functional State of Myocardium After Application of a Non-Cellular Allogenic Material for Stimulation of Regeneration Capacity in Experimental Infarction

“…Анало-гичные данные сообщают и другие исследователи [9,10]. Отсутствие потенциации инотропного ответа после периодов покоя или отрицательная динамика зависимости инотропной реакции от длительности периодов покоя обусловлены изменением в работе систем, ответственных за поддержание внутрикле-точного гомеостаза ионов кальция [7,10]. Известно, что нарушение Са 2+ -аккумулирующей активности саркоплазматического ретикулума кардиомиоцитов является одним из патогенетических механизмов электрической нестабильности миокарда и угнетения его инотропных возможностей, в том числе и при сер-дечной недостаточности ишемического генеза [13].…”

“…Для этого прекращали электрическую стимуляцию мышц на 4, 6, 8, 10, 12, 16, 20, 30 и 60 сек (период покоя) [7]. Сопоставляли амплитуды регулярного и первого, после периода покоя, циклов сокращение-расслабление (рис.…”

“…Получали кривую механической реституции как зависимость между амплитудой первого после пери-ода покоя цикла сокращение-расслабление и дли-тельностью этих периодов. Такой методический под-ход позволяет оценить способность кардиомиоцитов освобождать и поглощать Са 2+ в ходе одиночного цикла сокращение-расслабление [7]. Результаты представлены в случае нормального распределения выборки в виде М±m, где M -сред-нее значение показателя, m -стандартной ошибки средней; в прочих случаях -медианы и проценти-лей, Me [25;75].…”