Active force generation contributes to the complexity of spontaneous activity and to the response to stretch of murine cardiomyocyte cultures.

Nayir, Seyma; Lacour, Stéphanie P; Kucera, Jan P (2022). Active force generation contributes to the complexity of spontaneous activity and to the response to stretch of murine cardiomyocyte cultures. The journal of physiology, 600(14), pp. 3287-3312. The Physiological Society 10.1113/JP283083

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Monolayer cultures of cardiac cells exhibit spontaneous electrical and contractile activity, as in a natural cardiac pacemaker. Beating variability in these preparations recapitulates the power-law behavior of heart rate variability in vivo. However, the effects of mechano-electrical feedback on beating variability are not yet fully understood. Using stretchable microelectrode arrays, we examined the effects of the contraction uncoupler blebbistatin and the non-specific stretch activated channel blocker streptomycin on beating variability and on stretch-induced changes of beat rate. Without stretch, blebbistatin decreased the spatial complexity of beating variability, while streptomycin had no effects. Both stretch and release transiently increased beat rate; blebbistatin attenuated the increase of beat rate upon stretch, while streptomycin had no effects. Active force generation contributes to the complexity of spatiotemporal patterns of beating variability and to the increase of beat rate upon mechanical deformation. Our study contributes to understanding how mechano-electric feedback influences heart rate variability. Cardiomyocyte cultures exhibit spontaneous electrical and contractile activity, as in a natural cardiac pacemaker. In such preparations, beat rate variability exhibits features similar to those of heart rate variability in vivo. Mechanical deformations and forces feedback on the electrical properties of cardiomyocytes, but it is not fully elucidated how this mechano-electrical interplay affects beating variability in such preparations. Using stretchable microelectrode arrays, we assessed the effects of the myosin inhibitor blebbistatin and the nonselective stretch-activated channel blocker streptomycin on beating variability and on the response of neonatal or foetal murine ventricular cell cultures against deformation. Spontaneous electrical activity was recorded without stretch and upon predefined deformation protocols (5% uniaxial and 2% equibiaxial strain, applied repeatedly for 1 min every 3 min). Without stretch, spontaneous activity originated from the edge of the preparations, and its site of origin switched frequently in a complex manner across the cultures. Blebbistatin did not change mean beat rate, but it decreased the spatial complexity of spontaneous activity. In contrast, streptomycin did not exert any manifest effects. During the deformation protocols, beat rate transiently increased upon stretch, but paradoxically also upon release. Blebbistatin attenuated the response to stretch, while this response was not affected by streptomycin. Therefore, our data support the notion that in a spontaneously firing network of cardiomyocytes, active force generation, rather than stretch-activated channels, is mechanistically involved in the complexity of the spatiotemporal patterns of spontaneous activity and in the stretch-induced acceleration of beating. Abstract figure legend Mechano-electric feedback modulates myocardial electrical function, including pacemaking. By growing monolayer cultures of spontaneously active murine cardiac cells on stretchable microelectrode arrays, we examined whether active contractions influence the spatiotemporal characteristics of beating variability and the effects of stretching on beat rate. Under control conditions (no stretch and no pharmacological agent), the origin of the electrical activity changed frequently. After blocking contractions with blebbistatin, the spatiotemporal pattern of electrical activity became less variable and less complex. Under control conditions (no pharmacological agent), stretching (and also releasing) the cardiomyocyte monolayers transiently increased beat rate. Blebbistatin attenuated the acceleration of beating upon stretch. In contrast, streptomycin had no detectable effects. Thus, active force generation is involved in determining beating variability in spontaneously active cardiac tissue. Possible mechanisms may include cellular processes that sense contraction and chemical messengers. Our study contributes to understanding how mechano-electric feedback influences heart rate variability. This article is protected by copyright. All rights reserved.

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