You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Self-Organization of Muscle Cell Structure and Function}
Article:
Abstract:
The organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomere to the muscle bundle. One possible strategy for solving this multiscale coupling problem is to physically constrain the muscle cells in microenvironments that potentiate the organization of their intracellular space. We hypothesized that boundary conditions in the extracellular space potentiate the organization of cytoskeletal scaffolds for directed sarcomeregenesis. We developed a quantitative model of how the cytoskeleton of neonatal rat ventricular myocytes organizes with respect to geometric cues in the extracellular matrix. Numerical results and in vitro assays to control myocyte shape indicated that distinct cytoskeletal architectures arise from two temporally-ordered, organizational processes: the interaction between actin fibers, premyofibrils and focal adhesions, as well as cooperative alignment and parallel bundling of nascent myofibrils. Our results suggest that a hierarchy of mechanisms regulate the self-organization of the contractile cytoskeleton and that a positive feedback loop is responsible for initiating the break in symmetry, potentiated by extracellular boundary conditions, is required to polarize the contractile cytoskeleton.
Introduction:
During biological development, evolving forms are marked by distinct functionalities. An interesting example is the organization of myofibrils in striated muscle cells. As the myocyte matures, the myofibrils are rearranged from an irregularly dispersed pattern into tightly organized bundles spanning the length, rather than the width, of the cell[1]. Although assembly of the myofibril from its molecular constituents has been extensively investigated[2],[3],[4], how myofibrils build this specialized architecture and its functional consequences remains unanswered. This is important because changes in muscle structure accompany not only morphogenesis, but also pathogenesis[5],[6]. Myofibrils mature in a force-dependent manner[7],[8],[9], suggesting that the contractility of a cell may play an important role in polarizing the myofibrillar network. This has been shown in nonmuscle cells where the cytoskeletal architecture within a geometrically-defined microcompartment becomes polarized with increasing tractional forces[10],[11]. Thus, we hypothesized that geometric cues in the extracellular matrix( ECM) can organize the intracellular architecture and potentiate directed myofibrillogenesis. Because of the difficulty in identifying de novo sarcomeres in primary harvest muscle cells in culture, one strategy for studying myofibrillogenesis is to coax the disassembly and reassembly of myofibrils by forcing myocytes to assume shapes that are not commonly observed in vivo using engineered substrates in vitro[10],[11]. To guide these experiments, we developed a computational model of myofibrillar patterning to show the sensitivity of the intracellular architecture to the extracellular space. With these tools, we sought to understand the critical events in the global assembly and organization of the contractile apparatus in cardiac myocytes. By comparing experimental results with our computational model, we were able to elucidate the role of maturing myofibrils, their parallel coupling, and their functional attachment to the focal adhesion assembly and how these processes are guided spatially by the boundary conditions imposed on the cell. After determining the roles of these parameters in myofibrillogenesis, we then expanded our model to test the functional implications of these architectures. We developed a novel method for micropatterning on soft substrates and were able to engineer myocyte shape on substrates that would allow us to measure the contractility of these artificial shapes and compare them with the model results. Together, these results suggest that the self-assembly and-organization of the contractile apparatus is facilitated by a symmetry-breaking event that is potentiated by either a geometric cue in the extracellular space or a random event in the intracellular space.
Discussion:
Muscle morphogenesis is a hierarchal, self-organizing process spanning from nanometer scale conformational changes in proteins to bundled fibers sometimes a meter in length. We reasoned that boundary constraints are a physical signal that is conserved over all of these length scales and spatially organizes this broad range of coupled structures. Based on previous experimental evidence[17],[26],[27],[28], we hypothesized that geometric cues in the extracellular space help organize the assembly of the contractile apparatus in the cytoplasm and developed computational and experimental models to recapitulate these events. We report that distinct cytoskeletal architectures arise from two temporally-ordered, organizational processes: the cooperative interaction between premyofibrils and focal adhesions, as well as the mutual alignment and parallel bundling of nascent myofibrils. Our model assumes that the assembly of FAs and the parallel bundling of actin based fibers is coupled by a positive feedback loop and that the growing force on the FA potentiates its structural reinforcement, as suggested by previous experimental work[7],[8],[9]. By modeling the amount of bound and unbound integrin and by marking the maturation of the premyofibril to a nascent myofibril simply by increased contractility, we are able to predict the organization of the contractile apparatus in cardiac myocytes cultured on engineered substrates in a computationally efficient manner. To achieve this efficiency, we ignore the details of the molecular constituents of the assembly of myofibrils[2],[3],[4]. However, we were able to account for all the dominant factors in a course grained manner as indicated by the match between all our models and experiments. By experimenting with our assumptions in silico and comparing them to data from in vitro experiments, our results suggest that the force that the myofibrillar bundle exerts on the substrate is fiber length-dependant[10],[11],[12] and that the adjacent myofibrils exert “torque” on one another to facilitate coupling[24], are necessary to describe how these myocytes build and organize their internal cytoskeleton relative to extracellular cues. Our computationally efficient model recapitulates the elegant protein choreography of the sarcomere assembly, where an ensemble of proteins assembles repetitively along the length of the actin fiber template. Several models of cell cytoskeleton assembly and mechanics have been reported and it is worthwhile to compare and contrast the efforts[14],[15],[29]. Our model is similar to the model by Novak and colleagues[16] in that we have used reaction kinetics to simulate the dynamic self-assembly and – organization of the cytoskeleton. These approaches differ from that of Deshpande, et al[14],[15],[16] who report a solid mechanics model and Pazek and colleagues[14],[15],[29] who use a mechanochemical model. All four of these models simulate the bound and free states of integrins in some form and also model the increasing stabilization, or maturation, of focal adhesions with increases in exerted force. The Despande and Pazek models offer detailed mechanical analysis of the cell-substrate interface, whereas our model, like the Novak model, does not. While the Pazek, et al., model does not recapitulate stress fibers, our model, like the Novak and Deshpande models, does. Our model accounts for the specialized case of the maturing striated muscle cell by mimicking the transition of a premyofibril to the nascent myofibril, modeled by an increased ability to generate tension. The Hammer and Novak models omit the fiber length-force assumption that is critical to our model's ability to recapitulate our experimental data. Similarly, the Desphande and Novak models explicitly do not account for mutual alignment of fibers, whereas ours does. Our model, like the Desphande et al. and Pazek models, calculates the load exerted on the substrate by the contracting cell, where the Desphande and Pazek models offer detailed descriptions of the solid mechanics at this interface. Both our model and that by Novak et al., are similar to larger scale models of myofibril adaptation in the left ventricle[30], in the assumption that there is a network of fibers where all integrins are connected to all other integrins. Each model, including the one reported herein, varies in approach and further work is required to test all of these models against experimental data as we have attempted. We were able to reproduce the results shown by Novak et al.,[16], who predicted that with no fiber tension-length dependence, and homogeneous boundary conditions the FAs would aggregate to the perimeter. However, as our in vitro work shows even with a homogeneous boundary condition, i. e. the circular cell, there occurs a symmetry break, therefore it is necessary to introduce fiber tension-length dependance and mutual alignment of fibers for in silico experiments. We can also utilize the model to explore the effect of cell boundary curvature, cell aspect ratios and combinations of multiple cells on the myofibril distribution, as well as the relative importance of mutual fiber alignment in three dimensions. Additionally, it will be possible to integrate our model with adhesion dynamics models using the same methods as Paszek et al., to explore integrin clustering with contractile cells on substrates with different material properties[29]. This combination of a mechanical model with our myofibrillogenesis model could also allow for simulations of the rearrangement of the extracellular matrix by contractile cells. In summary, our study suggests that hierarchal organization of muscle requires localized cues that guide myofibrillogenesis. Specifically, a local symmetry break is required to potentiate the assembly and organization of FA and actin complexes that are the template for myofibrillar organization. Such cytoskeletal symmetry-breaking has also been widely observed in other important biological behaviors such as cellular migration[11], cellular division[31], and formation of tissue sheets[32]. The symmetry-breaking can arise from a static, external cue, such as a geometric feature in the boundary conditions imposed on the cell, or from a dynamic internal cue, such as a local overlapping of long fibers. The multiple time scales of these interacting events suggest a hierarchy of post-translational, self-organizational processes that are required for coupling cellular form and function.
How muscle is organized impacts its function . However , understanding how muscle organizes is challenging , as the process occurs over several length scales . We approach this multiscale coupling problem by constraining the overall shapes of muscle cells to indirectly control the organization of their intracellular space . We hypothesized the cellular boundary conditions direct the organization of cytoskeletal scaffolds . We developed a model of how the cytoskeleton of cardiomyocytes organizes with respect to boundary cues . Our computational and experimental results to control myocyte shape indicated that distinct muscle architectures arise from two main organizational mechanisms: the interaction between actin fibers , premyofibrils and focal adhesions , as well as cooperative alignment and parallel bundling of more mature myofibrils . We show that a hierarchy of processes regulate the self-organization of cardiomyocytes . Our results suggest that a symmetry break , due to the boundary conditions imposed on the cell , is responsible for polarization of the contractile cytoskeletal organization .