FiberSim: A flexible open-source model of myofilament-level contraction

Kosta, Sarah; Colli, Dylan; Ye, Qiang; Campbell, Kenneth S.

doi:10.1016/j.bpj.2021.12.021

Cited by 28 publications

(33 citation statements)

References 29 publications

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“…To identify mechanisms for depressed myocyte length-dependent tension, we used a spatially explicit half sarcomere model based on the opensource program FiberSim 23 , assuming a three-state kinetic model for thick filament activation. Two other conditions were tested; both prevented recruitment of SRX heads to DRX, with one further increasing the percent of SRX.…”

Section: Resultsmentioning

confidence: 99%

“…Numerical simulations of tension-calcium, tension-power/velocity, and tension-length relationships were performed via FiberSim, 23 a spatially explicit model of myofilament-level contraction. Thick filament kinetics were simulated as described by Kosta et al 23 using a scheme with an SRX state, a DRX state, and a single actin-attached state. The probability of heads transitioning from the SRX to the DRX state increased linearly with force.…”

Section: Methodsmentioning

confidence: 99%

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Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure with Pulmonary Hypertension

Jani

Aslam

Fenwick

et al. 2023

Preprint

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Rationale: Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in heart failure patients with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. Objective: To determine components of myocyte contractile depression in HFrEF-PH, identify those reflected by clinical RV indices, and elucidate their underlying biophysical mechanisms. Methods and Results: Resting, calcium- and load-dependent mechanics were measured in permeabilized RV cardiomyocytes isolated from explanted hearts from 23 HFrEF-PH patients undergoing cardiac transplantation and 9 organ-donor controls. Unsupervised machine learning using myocyte mechanical data with the highest variance yielded two HFrEF-PH subgroups that in turn mapped to patients with depressed (RVd) or compensated (RVc) clinical RV function. This correspondence was driven by reduced calcium-activated isometric tension in RVd, while surprisingly, many other major myocyte contractile measures including peak power, maximum unloaded shortening velocity, and myocyte active stiffness were similarly depressed in both groups. Similar results were obtained when subgroups were first defined by clinical indices, and then myocyte mechanical properties in each group compared. To test the role of thick-filament defects, myofibrillar structure was assessed by X-ray diffraction of muscle fibers. This revealed more myosin heads associated with the thick filament backbone in RVd but not RVc, as compared to controls. This corresponded to reduced myosin ATP turnover in RVd myocytes, indicating less myosin in a cross-bridge ready disordered-relaxed (DRX) state. Altering DRX proportion (%DRX) affected peak calcium-activated tension in the patient groups differently, depending on their basal %DRX, highlighting potential roles for precision-guided therapeutics. Lastly, increasing myocyte preload (sarcomere length) increased %DRX 1.5-fold in controls but only 1.2-fold in both HFrEF-PH groups, revealing a novel mechanism for reduced myocyte active stiffness and by extension Frank-Starling reserve in human HF. Conclusions: While there are multiple RV myocyte contractile deficits In HFrEF-PH, clinical indices primarily detect reduced isometric calcium-stimulated force related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure with Pulmonary Hypertension

Jani

Aslam

Fenwick

et al. 2023

Preprint

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“…Importantly, our model suggests that the phosphorylation/dephosphorylation kinetics of cMyBP-C are controlled via a conformational switch in the phosphorylatable m-motif itself. Although further experimental confirmation is required, the potential reciprocal relationships between m-motif structure, phosphorylation state and sarcomere function raise the intriguing possibility of a mechano-biochemical feedback loop: assuming that the forces developed during the contractile cycle acting on cMyBP-C have the capability of changing the conformation of the m-motif (36), such forces might alter the phosphorylation state of cMyBP-C which, as a key parameter of sarcomere function, would in turn affect force dynamics. In line with this idea, phosphorylation-dependent structural unfolding of the m-motif of cMyBP-C (26, 27) and changes in cMyBP-C phosphorylation following mechanical stress have been reported previously (37, 38).…”

Section: Discussionmentioning

confidence: 99%

“…However, the relationship between conformation and phosphorylation seems reciprocal and how exactly force affects m-motif structure and phosphorylation state of cMyBP-C in the intact sarcomere is not yet known, thus the effects and details of such feedback regulation remain to be elucidated. A promising first approach to do so might be to interface our current model with existing models of sarcomere dynamics (36, 39, 40).…”

Section: Discussionmentioning

confidence: 99%

The cardiac myosin binding protein-C phosphorylation state as a function of multiple protein kinase and phosphatase activities

Kampourakis

Ponnam

Koch³

2023

Preprint

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Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) is a crucial determinant of cardiac myofilament function. Although cMyBP-C phosphorylation by various protein kinases has been extensively studied, the influence of protein phosphatases on cMyBP-C's multiple phosphorylation sites has remained largely obscure. Here we provide a detailed biochemical characterization of cMyBP-C dephosphorylation by protein phosphatases 1 and 2A (PP1 and PP2A) and develop an integrated kinetic model for cMyBP-C phosphorylation using data for both PP1, PP2A and protein kinases A (PKA), C and RSK2. We find strong site-specificity and a hierarchical mechanism for both phosphatases, proceeding in the opposite direction of sequential phosphorylation by PKA. The model is consistent with published data from human patients and predicts complex non-linear cMyBP-C phosphorylation patterns that are validated experimentally. Our results emphasize the importance of phosphatases for cMyBP-C regulation and prompt us to propose reciprocal relationships between cMyBP-C m-motif conformation, phosphorylation state and myofilament function.

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“…To better understand whether these functional and structural findings would have consequences on myosin recruitment, we ran molecular simulations. We applied a computational tool, FiberSim 2.1.0 (https://campbell-muscle-lab.github.io/FiberSim/), which is a spatially explicit myofilament model that is able to mimic the force generation [14]. When implementing an increase of the proportion of SRX myosin molecules by 10%, to decrease the DRX to SRX ratio by approximately a third (as it happens in DCM dogs when compared with NF animals), simulations showed a small decrease in isometric force (at maximal and sub-maximal activation levels) and a rightward shift of the Force-pCa curve leading to a lower Ca 2+ sensitivity (Fig.…”

Section: Higher Proportion Of Myosin Molecules In the Srx Conformatio...mentioning

confidence: 99%

Predominant myosin super-relaxed state in canine myocardium with naturally occurring dilated cardiomyopathy

Ochala

Lewis

Beck

et al. 2023

Preprint

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Dilated cardiomyopathy (DCM) is a naturally occurring heart failure condition in humans and dogs, notably characterized by a reduced ejection fraction. As the identification of the underlying cellular and molecular mechanisms remain incomplete, the aim of the present study was to assess whether myosin and its known relaxed conformational states contribute to DCM aetiology. For that, we dissected and skinned thin cardiac strips from left ventricle obtained from six DCM Doberman Pinschers and six nonfailing controls (NF). We then used Mant-ATP chase experiments, X-ray diffraction and molecular simulations. We observed that, in DCM dogs, the amount of myosin heads in the stabilizing conformational state also known as super-relaxed (SRX) is significantly increased when compared with NF dogs. We also found that myosin heads are blocked in this SRX state preventing a proper length dependent activation, subsequently hindering myosin head recruitment and force-generating capacity. Despite these, our data also demonstrate that when applying EMD-57033, a small molecule activating myosin, SRX-related detrimental effects can be rescued. Taken together, our results suggest that myosin SRX contributes to the DCM pathophysiology and that the observed negative changes are reversible, giving hope for a myosin-centered pharmacological treatment of this particular cardiac disease.

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FiberSim: A flexible open-source model of myofilament-level contraction

Cited by 28 publications

References 29 publications

Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure with Pulmonary Hypertension

Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure with Pulmonary Hypertension

The cardiac myosin binding protein-C phosphorylation state as a function of multiple protein kinase and phosphatase activities

Predominant myosin super-relaxed state in canine myocardium with naturally occurring dilated cardiomyopathy

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