Biology subjects

Jezek, F.

Publications and source records attributed to Jezek, F..

4 recordsLinked to original sources

bioRxiv2025

Multiscale Computational Modeling of the Cardiopulmonary Consequences of Postnatal Hyperoxia with Implications for Preterm Born Children

Moderate to extreme preterm birth (<32 weeks gestation) affects cardiopulmonary structure and function and is associated with increased risk of heart failure through adulthood. The rat hyperoxia (Hx) model (term born; postnatal Hx exposure) captures biventricular changes, including at the cell- and organ-scale, and pulmonary vascular remodeling seen in preterm humans. However, synthesizing these measures across scales and organ systems is challenging. We hypothesized that in-silico modeling of biventricular mitochondrial, myofiber, and organ-scale function plus circulatory function could capture key features of cardiopulmonary abnormalities due to preterm birth. Therefore, we calibrated a multiscale model to subject-specific biventricular pressure-volume data previously obtained from Hx rats alongside normoxic (Nx) controls to investigate the abnormalities in cardiopulmonary function at multiple scales in this animal model of human preterm birth. The calibrated model demonstrates excellent agreement with the data and captures the expected pulmonary vascular changes and right ventricular dilation seen in preterm born children. Our multiscale modeling approach captures cardiopulmonary abnormalities across spatial scales and provides an innovative approach to explore the consequences of preterm birth beyond preclinical experimental data alone. This is a foundational step in understanding the impact of preterm birth on cardiopulmonary disease in childhood as well as adulthood.

bioengineering↗

bioRxiv2025

Kinetic Modeling of mant-ATP Turnover to Interpret the Biochemically Defined Myosin Super-Relaxed State

The fluorescent ATP analog mant-ATP has become a valuable tool for quantifying occupancy of the myosin super-relaxed (SRX) state, a biochemically inactive state of myosin in striated muscle. Interpretation of mant-ATP fluorescence decay kinetics is confounded by inconsistencies in state definitions and kinetic assumptions. Here, we develop a mass-action kinetic model of myosin cross-bridge cycling and mant-ATP turnover to reconcile these discrepancies and provide a mechanistic framework for interpreting SRX measurements. Our model simulates ATP label-chase experiments and demonstrates that conventional double-exponential fitting methods do not directly quantify SRX occupancy. Instead, we show that slow and fast decay phases of mant-ATP fluorescence arise from label redistribution among kinetically distinct states, not state populations in equilibrium. The model resolves several apparent paradoxes identified in recent studies by reproducing experimental observations without requiring SRX and DRX kinetic isolation or implausible equilibrium constants. Simulations further quantify the impact of experimental factors--such as ADP accumulation, photobleaching, and initial rigor state occupancy--on fluorescence kinetics and SRX estimates. These results support a revised framework for SRX quantification and suggest that label-chase experiments must be interpreted using mechanistic models to accurately assess myosin state distributions and transition kinetics. SIGNIFICANCEThe relative occupancy of myosin in the super-relaxed state (SRX) is a key determinant of basal ATP turnover in muscle. Measurement of ATP exchange using the fluorescent analog mant-ATP is used to assess the relative population of myosin in the SRX versus the disordered relaxed (DRX) state. Existing approaches to analyzing data from these experiments use double exponential fits to represent the mant-ATP decay in the chase-phase of the experiment. However, quantitative and mechanistic interpretations based on these analyses remain ambiguous. We present a mechanistic model of myosin ATP turnover that reproduces observed fluorescence decays under defined conditions. The results indicate that conventional interpretations, while qualitatively reasonable, are quantitatively inconsistent, as the observed slow and fast phases are predicted to arise from ligand redistribution rather than distinct equilibrium states. This framework enables rigorous, model-based interpretation of mant-ATP assays to help clarify how myosin kinetics are reflected in mant-ATP loading-chase experiments and experimental conditions may influence apparent SRX kinetics.

biophysics↗

bioRxiv2025

Ca2+ increases cardiac muscle viscoelasticity independent of active force development

In addition to activation of muscle contraction by Ca2+, recent studies suggest that Ca2+ also affects muscle passive mechanical properties. The goal of this study was to determine if Ca2+ regulates the stiffness of cardiac muscle, independent of active contraction. The mechanical response to stretch for mouse demembranated cardiac trabeculae was probed at different Ca2+ levels after eliminating active contraction using a combination of two myosin ATPase inhibitors: para-nitroblebbistatin (PNB, 50 M), plus mavacampten (Mava, 50 M). Myocardial force level was assessed during large stretches ({asymp} 20% initial muscle length) with a range of stretch velocities. For relaxed muscle, in response to stretch, muscle force rose to a peak and then decayed toward a lower steady-state level, consistent with the viscoelastic nature of cardiac muscle. Peak force was higher with faster stretch velocity, but the steady-state force was independent of stretch velocity, consistent with the presence of both apparent viscous and elastic components of the stretch response. In the presence of the inhibitors PNB plus Mava, when Ca2+ level was increased, active contraction was completely prevented. However, the viscoelastic force response to stretch was markedly increased by high Ca2+ and was > 6-fold higher than at low Ca2+ level. The relationship of viscous force to Ca2+ level had a similar form to the relationship of active force to Ca2+ (measured in the absence of inhibitors), suggesting a common regulatory mechanism is involved. As expected, Ca2+-activated contraction was inhibited by lowering the temperature from 21{degrees}C to 10{degrees}C. In contrast, the Ca2+-activated viscous property was not inhibited at lower temperature, further suggesting that active contraction and the viscous property involve distinct mechanisms. This study demonstrates that in addition to triggering activation of contraction, Ca2+ also increases the apparent viscous property of cardiac muscle. New and NoteworthyCa2+ is well-known to trigger activation of muscle contraction. This study demonstrates a new mechanical role for Ca2+ in cardiac muscle involving a >6-fold increase in the apparent muscle viscoelasticity. Activation of a viscous element by Ca2+ might influence the mechanical properties of activated cardiac muscle.

biophysics↗

bioRxiv2025

Theoretical Analysis of Power-Law Stress Relaxation and Calcium-Dependent Passive Mechanics in Cardiac Muscle

This study investigates the passive viscoelastic mechanical properties of cardiac muscle by introducing a theoretical model that explains the power-law kinetics of passive stress decay. The model accounts for two parallel processes contributing to passive mechanics: an elastic component and a viscoelastic component designed to simulate stress/strain-mediated unfolding of serial domains in the titin molecule. Under stress, serial globular domains within the elastic region of the titin molecule reversibly unfold. This unfolding phenomenon contributes to both hysteresis (a lag in stress between loading and unloading) and preconditioning effects in simulated striated muscle mechanics. Moreover, experimental evidence indicates that stress relaxation in cardiac muscle follows a power law, and that the muscles nonlinear stress-strain relationship and hysteresis behavior are calcium-dependent. To analyze these mechanical phenomena, we simulate the apparent viscous element as a mesoscopic-scale ensemble of chains, each composed of serial globular domains that unfold in a stress-dependent manner. Although the model was developed to represent the behavior of titin, it equivalently represents any contributing process involving a linked series of domains that undergo stress-mediated unfolding. By providing a unified basis for the observed viscoelastic and preconditioning effects, calcium dependency, and power-law stress relaxation phenomena, this study offers a novel theoretical basis for understanding and simulating the role of titin in striated muscle mechanics. 1 Key pointsO_LIPassive stress relaxation of cardiac muscle follows a power-law decay, a phenomenon that is explained using a theoretical model of dynamic unfolding of globular domains along polymer chain. C_LIO_LIThe theoretical model simulates the behavior of titin, a giant sarcomere protein linking myosin thick filaments to the Z disk and providing passive restoring force during muscle stretch. C_LIO_LIThe theoretical model is able to account the observed effects of calcium on the effective viscoelastic passive mechanics of cardiac muscle. C_LIO_LIThis model provides a theoretical basis for understanding passive visocelastic properties and titins role in striated muscle mechanics. C_LI

biophysics↗