Regional variation in myofilament length-dependent activation

Cazorla, Olivier; Lacampagne, Alain

doi:10.1007/s00424-011-0933-6

Cited by 27 publications

(32 citation statements)

References 107 publications

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“…The heart is known to manifest regional heterogeneity, with reports of transmural differences between the endocardium and epicardium in voltage-gated K ϩ currents (2), action potential duration (14), excitation-contraction coupling (7), myosin light chain kinase abundance (5), and myofilament properties (3,4,25). We have previously reported that ␣ 1 -ARs mediated fundamentally different inotropic responses in the RV versus LV myocardium (27,28).…”

Section: Discussionmentioning

confidence: 97%

Intraventricular and interventricular cellular heterogeneity of inotropic responses to α₁-adrenergic stimulation

Chu

Thai

Park

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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α1-Adrenergic receptors (α1-ARs) elicit a negative inotropic effect (NIE) in the mouse right ventricular (RV) myocardium but a positive inotropic effect (PIE) in the left ventricular (LV) myocardium. Effects on myofilament Ca(2+) sensitivity play a role, but effects on Ca(2+) handling could also contribute. We monitored the effects of α1-AR stimulation on contraction and Ca(2+) transients using single myocytes isolated from the RV or LV. Interestingly, for both the RV and LV, we found heterogeneous myocyte inotropic responses. α1-ARs mediated either a PIE or NIE, although RV myocytes had a greater proportion of cells manifesting a NIE (68%) compared with LV myocytes (36%). Stimulation of a single α1-AR subtype (α1A-ARs) with a subtype-selective agonist also elicited heterogeneous inotropic responses, suggesting that the heterogeneity arose from events downstream of the α1A-AR subtype. For RV and LV myocytes, an α1-AR-mediated PIE was associated with an increased Ca(2+) transient and a NIE was associated with a decreased Ca(2+) transient, suggesting a key role for Ca(2+) handling. For RV and LV myocytes, α1-AR-mediated decreases in the Ca(2+) transient were associated with increased Ca(2+) export from the cell and decreased Ca(2+) content of the sarcoplasmic reticulum. In contrast, for myocytes with α1-AR-induced increased Ca(2+) transients, sarcoplasmic reticulum Ca(2+) content was not increased, suggesting that other mechanisms contributed to the increased Ca(2+) transients. This study demonstrates the marked heterogeneity of LV and RV cellular inotropic responses to stimulation of α1-ARs and reveals a new aspect of biological heterogeneity among myocytes in the regulation of contraction.

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Section: Discussionmentioning

confidence: 97%

Intraventricular and interventricular cellular heterogeneity of inotropic responses to α₁-adrenergic stimulation

Chu

Thai

Park

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Recent experimental data have shown heterogeneity in length dependence [31]. However, the implications of this effect on whole organ pump function are still unclear.…”

Section: Transmural Heterogeneitymentioning

confidence: 99%

“…Changes in such 'isoform' proportions over time have been observed across species in response to chronic cardiac stress [30], and the protein has also been implicated in ischaemic human heart disease [34]. Studies in recent years have uncovered more data on this important protein in experiments on both wild-type and genetically modified mice [22,31,35], although its functional role in the beating heart remains debated. Section 4.1 provides an example of an application of the VPM model to investigate the heterogeneity of tension generation in light of the previous experimental results and modelling predictions described in this section.…”

Section: Hypothesis Testing In the Mouse Heart Modelmentioning

confidence: 99%

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Integrating multi-scale data to create a virtual physiological mouse heart

et al. 2013

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One contribution of 25 to a Theme Issue 'The virtual physiological human: integrative approaches to computational biomedicine'. While the virtual physiological human (VPH) project has made great advances in human modelling, many of the tools and insights developed as part of this initiative are also applicable for facilitating mechanistic understanding of the physiology of a range of other species. This process, in turn, has the potential to provide human relevant insights via a different scientific path. Specifically, the increasing use of mice in experimental research, not yet fully complemented by a similar increase in computational modelling, is currently missing an important opportunity for using and interpreting this growing body of experimental data to improve our understanding of cardiac function. This overview describes our work to address this issue by creating a virtual physiological mouse model of the heart. We describe the similarities between human-and mouse-focused modelling, including the reuse of VPH tools, and the development of methods for investigating parameter sensitivity that are applicable across species. We show how previous results using this approach have already provided important biological insights, and how these can also be used to advance VPH heart models. Finally, we show an example application of this approach to test competing multi-scale hypotheses by investigating variations in length-dependent properties of cardiac muscle.

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“…However, the molecular mechanisms and cellular signal transduction processes that underlie these cellular regulatory systems are still under intense investigation [9]. In this issue, this area of research is reviewed by contributions from the groups of Campbell [5], Cazorla [6], Cingolani [7], Peter Kohl [2], Landesberg [23], and McDonald [16].…”

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confidence: 99%

The cytoskeleton and the cellular transduction of mechanical strain in the heart: a special issue

Tombe

Granzier

2011

Pflugers Arch - Eur J Physiol

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There is a fundamental requirement for all cells to communicate and process information with regard to their surroundings and this is accomplished by vast array of signals that, at its basis, are all based on four principal physical processes: electricity, force, chemical reaction, and light. Mechanical strain sensing in muscle is unique in that forces are both generated by the muscle cells itself ("insideout" pathway) as well as acted upon these cells from the exterior ("outside-in" pathway). These mechanisms are critically important in the heart to alter its form and function and meet varied hemodynamic demands. Accordingly, this special issue of Pflüger´s Archiv European Journal of Physiology is focused on the cellular transduction of mechanical strain in the heart. The issue is composed of invited reviews written by world leaders in their respective fields of research.A well-known example of acute strain regulation in cardiac tissue is the Frank-Starling Law of the heart [9]. Interestingly, although this basic beat-to-beat regulatory mechanism has been appreciated for over a century, the cellular mechanisms that underlie this strain transduction system have only been identified in recent decades as being caused by (a) an immediate change in cardiac cell contractility that is secondary to changes in contractile protein Ca 2+ sensitivity [11,12], and (b) a slower change in cardiac cell contractility that develops over the course of several beats that is secondary to changes in intracellular Ca 2+ homeostasis [1,17]. However, the molecular mechanisms and cellular signal transduction processes that underlie these cellular regulatory systems are still under intense investigation [9]. In this issue, this area of research is reviewed by contributions from the groups of Campbell Cardiac muscle cells are dynamic; increased mechanical load induces a hypertrophic response, while reduced load elicits the reverse response [21]. The cellular signal transduction processes responsible for this tight, long term, regulatory system that leads to remodeling of the sarcomeric architecture in the cardiac muscle cell are varied and complex. In addition, the cardiac cell is integrated into the extracellular scaffolding and force transmission system formed by the extracellular matrix, which itself is a dynamic structure that is subject to regulation and remodeling. This rapidly expanding area of research is reviewed in this special issue by contributions from the groups of Borg [3], Kresh [13], Parker [15], and Russell [8].Among the several cytoskeletal protein structures that play a role in the cellular transduction system, the giant sarcomeric protein titin (the "fourth filament") is particularly intriguing. Titin's role as the predominant contributor to passive force generation within the physiological range in striated muscle is now well established [14]. However, recent observations indicate a far greater role of this giant protein in a vast array of cellular functions, including the response to cellular strain in myofilament l...

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Regional variation in myofilament length-dependent activation

Cited by 27 publications

References 107 publications

Intraventricular and interventricular cellular heterogeneity of inotropic responses to α₁-adrenergic stimulation

Intraventricular and interventricular cellular heterogeneity of inotropic responses to α₁-adrenergic stimulation

Integrating multi-scale data to create a virtual physiological mouse heart

The cytoskeleton and the cellular transduction of mechanical strain in the heart: a special issue

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Regional variation in myofilament length-dependent activation

Cited by 27 publications

References 107 publications

Intraventricular and interventricular cellular heterogeneity of inotropic responses to α1-adrenergic stimulation

Intraventricular and interventricular cellular heterogeneity of inotropic responses to α1-adrenergic stimulation

Integrating multi-scale data to create a virtual physiological mouse heart

The cytoskeleton and the cellular transduction of mechanical strain in the heart: a special issue

Contact Info

Product

Resources

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Intraventricular and interventricular cellular heterogeneity of inotropic responses to α₁-adrenergic stimulation

Intraventricular and interventricular cellular heterogeneity of inotropic responses to α₁-adrenergic stimulation