The slow force response to stretch: Controversy and contradictions

Abstract

When exposed to an abrupt stretch, cardiac muscle exhibits biphasic active force enhancement. The initial, instantaneous, force enhancement is well explained by the Frank-Starling mechanism. However, the cellular mechanisms associated with the second, slower phase remain contentious. This review explores hypotheses regarding this "slow force response" with the intention of clarifying some apparent contradictions in the literature. The review is partitioned into three sections. The first section considers pathways that modify the intracellular calcium handling to address the role of the sarcoplasmic reticulum in the mechanism underlying the slow force response. The second section focuses on extracellular calcium fluxes and explores the identity and contribution of the stretch-activated, nonspecific, cation channels as well as signalling cascades associated with G-protein coupled receptors. The final section introduces promising candidates for the mechanosensor(s) responsible for detecting the stretch perturbation. K E Y W O R D SAnrep effect, cardiac mechanosensitivity, signalling pathway, slow force response

Disruption of transverse‐tubular network reduces energy efficiency in cardiac muscle contraction

“…30,31 The effects of detubulation mimic several features of mechanical dysfunction in heart failure, specifically the reduction of active force production particularly at high rates of contraction, 30 and in addition to abolition of the cardiac slow force response to abrupt stretch. 31 These results demonstrate that disruption of the mechanosensitive channels and exchangers on the t-tubules, coupled with the disturbance of the ATPase activity, impair mechanosensor signalling cascades, 32 leading to the reduced production of force by crossbridges in response to a change in an intervention including a change of stimulus frequency 30 and muscle length. 31 From the above description of altered Ca 2+ dynamics and impaired force response upon detubulation, we hypothesize that detubulation affects energy utilization for the cycling of Ca 2+ in activating contraction and for the cycling of crossbridges in effecting contraction.…”

Insights From Computational Modeling Into the Contribution of Mechano-Calcium Feedback on the Cardiac End-Systolic Force-Length Relationship

“…The THR model of excitation-contraction utilizes a simple phenomenological model of rat cardiac electrophysiology to capture the action potential waveform, and couples it to detailed biophysical models of Ca 2+ handling and cross-bridge kinetics. The phenomenological nature of the action potential waveform means that electrophysiological length-dependent pathways, such as stretch-activated channels (SACs) which underlie the slow force response (Calaghan and White, 2004;Niederer and Smith, 2007;Dowrick et al, 2019), are not explicitly captured. But despite their absence, the THR model is able to reproduce the widely observed difference in isometric and work-loop ESFLRs, suggesting that length-dependent electrophysiological pathways play a minor role, if any, in eliciting this phenomenon.…”

CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect

“…1999; Dowrick et al . 2019). Additionally, SFR is mediated by SACs and can be inhibited in mice by streptomycin (Ward et al .…”

“…1999; Dowrick et al . 2019), although Sarnoff et al . (1960) did not consider this stretch per se essential for triggering the Anrep effect.…”

“…The mechanistic subcellular background of SFR includes increased intracellular Ca 2+ transient either activated by the non‐specific stretch‐activated ion channels (SACs) and/or by the stretch‐activated G‐protein coupled angiotensin and endothelin receptor, working both via the Na + /H + and Na + /Ca 2+ exchanger (Calaghan & White, 2004; Dowrick et al . 2019). This is considered as a valid mechanism for the Anrep effect (Alvarez et al .…”