The passive mechanical response of skeletal muscles at fast time scales is dominated by long range interactions inducing cooperative behavior without breaking the detailed balance. This leads to such unusual "material properties" as negative equilibrium stiffness and different behavior in force and displacement controlled loading conditions. Our fitting of experimental data suggests that "muscle material" is finely tuned to perform close to a critical point which explains large fluctuations observed in muscles close to the stall force.

Complex 3D beating heart models are now available, but their complexity makes calibration and validation very difficult tasks. We thus propose a systematic approach of deriving simplified reduced-dimensional models, in "0D"-typically, to represent a cardiac cavity, or several coupled cavities-and in "1D"-to model elongated structures such as muscle samples or myocytes. We apply this approach with an earlier-proposed 3D cardiac model designed to capture length-dependence effects in contraction, which we here complement by an additional modeling component devised to represent length-dependent relaxation. We then present experimental data produced with rat papillary muscle samples when varying preload and afterload conditions, and we achieve some detailed validations of the 1D model with these data, including for the length-dependence effects that are accurately captured. Finally, when running simulations of the 0D model pre-calibrated with the 1D model parameters, we obtain pressure-volume indicators of the left ventricle in good agreement with some important features of cardiac physiology, including the so-called Frank-Starling mechanism, the End-Systolic Pressure-Volume Relationship, as well as varying elastance properties. This integrated multi-dimensional modeling approach thus sheds new light on the relations between the phenomena observed at different scales and at the local versus organ levels.

In this paper we report, clarify and broaden various recent efforts to complement the chemistry-centered models of force generation in (skeletal) muscles by mechanics-centered models. The physical mechanisms of interest can be grouped into two classes: passive and active. The main passive effect is the fast force recovery which does not require the detachment of myosin cross-bridges from actin filaments and can operate without a specialized supply of metabolic fuel (ATP). In mechanical terms, it can be viewed as a collective folding-unfolding phenomenon in the system of interacting bi-stable units and modeled by near equilibrium Langevin dynamics. The active force generation mechanism operates at slow time scales, requires detachment and is crucially dependent on ATP hydrolysis. The underlying mechanical processes take place far from equilibrium and are represented by stochastic models with broken time reversal symmetry implying non-potentiality, correlated noise or multiple reservoirs. The modeling approaches reviewed in this paper deal with both active and passive processes and support from the mechanical perspective the biological point of view that phenomena involved in slow (active) and fast (passive) force generation are tightly intertwined. They reveal, however, that biochemical studies in solution, macroscopic physiological measurements and structural analysis do not provide by themselves all the necessary insights into the functioning of the organized contractile system. In particular, the reviewed body of work emphasizes the important role of long-range interactions and criticality in securing the targeted mechanical response in the physiological regime of isometric contractions. The importance of the purely mechanical micro-scale modeling is accentuated at the end of the paper where we address the puzzling issue of the stability of muscle response on the so called 'descending limb' of the isometric tetanus.

SNARE proteins zipper to form SNAREpins that power vesicle fusion with target membranes in a variety of biological processes. A single SNAREpin takes about 1 second to fuse two bilayers, yet a handful can ensure release of neurotransmitters from synaptic vesicles much faster, in a 10th of a millisecond. We propose that, similar to the case of muscle myosins, the ultrafast fusion results from cooperative action of many SNAREpins. The coupling originates from mechanical interactions induced by confining scaffolds. Each SNAREpin is known to have enough energy to overcome the fusion barrier of 25-35 k B T, however, the fusion barrier only becomes relevant when the SNAREpins are nearly completely zippered and from this state each SNAREpin can deliver only a small fraction of this energy as mechanical work. Therefore they have to act cooperatively and we show that at least 3 of them are needed to ensure fusion in less than a millisecond. However, to reach the pre-fusion state collectively, starting from the experimentally observed half-zippered metastable state, the SNAREpins have to mechanically synchronize which takes exponentially longer time as the number of SNAREpins increases. Incorporating this somewhat counter-intuitive idea in a simple coarse grained model results in the novel prediction that there should be an optimum number of SNAREpins for sub-ms fusion: 3-6 over a wide range of parameters. Interestingly, in situ cryo-electron microscope tomography has very recently shown that exactly six SNAREpins participate in the fusion of each synaptic vesicle. This number is in the range predicted by our theory.

The chemomechanical model of Huxley and Simmons (HS) [A. F. Huxley and R. M. Simmons, Nature 233, 533 (1971)NATUAS0028-083610.1038/233533a0] provides a paradigmatic description of mechanically induced collective conformational changes relevant in a variety of biological contexts, from muscles power stroke and hair cell gating to integrin binding and hairpin unzipping. We develop a statistical mechanical perspective on the HS model by exploiting a formal analogy with a paramagnetic Ising model. We first study the equilibrium HS model with a finite number of elements and compute explicitly its mechanical and thermal properties. To model kinetics, we derive a master equation and solve it for several loading protocols. The developed formalism is applicable to a broad range of allosteric systems with mean-field interactions.

Mechanically induced unfolding of passive crosslinkers is a fundamental biological phenomenon encountered across the scales from individual macro-molecules to cytoskeletal actin networks. In this paper we study a conceptual model of athermal load-induced unfolding and use a minimalistic setting allowing one to emphasize the role of long-range interactions while maintaining full analytical transparency. Our model can be viewed as a description of a parallel bundle of N bistable units confined between two shared rigid backbones that are loaded through a series spring. We show that the ground states in this model correspond to synchronized, single phase configurations where all individual units are either folded or unfolded. We then study the fine structure of the wiggly energy landscape along the reaction coordinate linking the two coherent states and describing the optimal mechanism of cooperative unfolding. Quite remarkably, our study shows the fundamental difference in the size and structure of the folding-unfolding energy barriers in the hard (fixed displacements) and soft (fixed forces) loading devices which persists in the continuum limit. We argue that both, the synchronization and the non-equivalence of the mechanical responses in hard and soft devices, have their origin in the dominance of long-range interactions. We then apply our minimal model to skeletal muscles where the power-stroke in acto-myosin crossbridges can be interpreted as passive folding. A quantitative analysis of the muscle model shows that the relative rigidity of myosin backbone provides the long-range interaction mechanism allowing the system to effectively synchronize the power-stroke in individual crossbridges even in the presence of thermal fluctuations. In view of the prototypical nature of the proposed model, our general conclusions pertain to a variety of other biological systems where elastic interactions are mediated by effective backbones

We propose a chemical-mechanical model of myosin heads in sarcomeres, within the classical description of rigid sliding filaments. In our case, myosin heads have two mechanical degrees-of-freedom (dofs)one of which associated with the so-called power stroke-and two possible chemical states, i.e. bound to an actin site or not. Our major motivations are twofold: (1) to derive a multiscale coupled chemical-mechanical model, and (2) to thus account-at the macroscopic scale-for mechanical phenomena that are out of reach for classical muscle models. This model is first written in the form of Langevin stochastic equations, and we are then able to obtain the corresponding Fokker-Planck partial differential equations governing the probability density functions associated with the mechanical dofs and chemical states. This second form is important, as it allows to monitor muscle energetics, and also to compare our model with classical ones, such as the Huxley'57 model to which our equations are shown to reduce under two different types of simplifying assumptions. This provides insight, and gives a Langevin form for Huxley'57. We then show how we can calibrate our model based on experimental data-taken here for skeletal muscles-and numerical simulations demonstrate the adequacy of the model to represent complex physiological phenomena, in particular the fast isomet

We study a simple micro-mechanical device that does not lose its snap-through behavior in an environment dominated by fluctuations. The main idea is to have several degrees of freedom that can cooperatively resist the de-synchronizing effect of random perturbations. As an inspiration we use the power stroke machinery of skeletal muscles, which ensures at sub-micron scales and finite temperatures a swift recovery of an abruptly applied slack. In addition to hypersensitive response at finite temperatures, our prototypical Brownian snap spring also exhibits criticality at special values of parameters which is another potentially interesting property for micro-scale engineering applications.