Data-driven modeling of sarcomere self-assembly and addition

• Applicant: Professor Dr. Benjamin M. Friedrich
• Subject Area: Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555765544

Every voluntary movement of our body is powered by the contraction of periodic acto-myosin bundles inside striated muscle cells termed myofibrils. Myofibrils are “active cytoskeletal crystals” with hundreds of stereotyped, micrometer-sized sarcomere units repeated in series. During muscle development, sarcomere self-assembly establishes a precise arrangement of polar actin filaments, bipolar myosin motor filaments, and accessory proteins in each sarcomere. This regular arrangement is key for their biological function. Despite enormous progress in understanding muscle physiology and the molecular composition and structure of sarcomeres, we still know little about the physical mechanisms that drive sarcomere self-assembly, and there are conflicting hypotheses about the underlying biophysical mechanisms. There is growing evidence that myofibrils originate from disordered acto-myosin bundles, which undergo a transition from nematic to smectic order, establishing periodic patterns with alternating localization of myosin and actin crosslinkers. A similar transition has been observed in stress fibers of non-muscle cells under atypical conditions, which is likewise not understood. We aim to identify physical mechanisms of sarcomere self-assembly by combining advanced image analysis and data-driven modeling. We will develop and deploy analysis tools including machine learning to identify correlated fluctuations and defects in developing sarcomeres from different model systems and species. This will allow us to refine hypotheses on the interactions between sarcomere components. We will test these hypotheses for their ability to self-assemble periodic sarcomeric patterns using agent-based simulations, and derive testable predictions under perturbations. We will pursue this ambitious goal within an established theory-experiment collaboration with the experimental Schnorrer group at IBDM. Our collaboration recently (i) showed that myosin and actin crosslinkers form periodic patterns first, while actin becomes patterned only hours later, which prompts modification of previous models, and (ii) identified a new mechanism of sarcomere addition by sarcomere division. For this project, the Schnorrer group already provided 3D multi-channel fluorescence microscopy images that cover the entire time course of myofibrillogenesis in the insect flight muscle, which shall be analyzed and form the basis for data-driven modeling here. The proposed work will showcase a prime example of self-organized pattern formation in the cytoskeleton characterized by a nematic-to-smectic order transition, and subsequent sarcomere addition during muscle fiber growth. Our fundamental research on sarcomerogenesis can form a basis for a better understanding of muscle regeneration and repair.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Dr. Frank Schnorrer