Regulation and mechanics of a homeostatic tension in reconstituted muscle tissue

• Applicant: Professor Dr. Timo Betz
• Subject Area: Biophysics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569108445

Muscle tissues are not only responsible for movement but also maintain posture, generate heat, and adapt to mechanical environments. Recent studies suggest that unstimulated ("homeostatic") tension plays a key role in muscle development, yet its regulation and mechanical basis remain poorly understood—particularly in diseases such as Duchenne Muscular Dystrophy (DMD). This project aims to establish and characterize homeostatic tension in reconstituted human muscle microtissues (MMTs) and uncover its mechanical and molecular underpinnings. Our preliminary data show that DMD-derived MMTs exhibit paradoxically higher homeostatic tension compared to healthy controls, despite reduced force during stimulated contractions. We hypothesize that this tension is an actively regulated mechanical setpoint, distinct from both passive tension and stimulated contractions. To test this, we will combine high-resolution imaging, force quantification, pharmacological interventions, and advanced micromechanical assays in a custom-built PMMA chamber system. We will dissect the contributions of cortical actomyosin, sarcomeres, and extracellular matrix to both homeostatic and stimulated tension, and study their rheological behavior under time- and frequency-dependent strain. Particular focus will be given to the misregulation observed in DMD tissues, to determine whether increased homeostatic tension originates from sarcomeric or cortical components. Moreover, we will explore the inverse relationship between homeostatic and stimulated tension, test for nonlinear stiffening, and quantify spatial strain distributions to identify affine versus non-affine mechanical behavior. The instrumentation will be extended to allow in-incubator force readouts and active rheology through closed-loop piezo-actuated post manipulation. Ultimately, this research will yield critical insights into the regulation and mechanical function of homeostatic tension in muscle tissue, inform muscle disease models, and enable the development of more physiologically accurate in vitro systems.

• DFG Programme: Research Grants