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Abstract Emerging in vivo evidence suggests that repeated muscle contraction, or exercise, impacts peripheral nerves. However, the difficulty of isolating the muscle‐specific impact on motor neurons in vivo, as well as the inability to decouple the biochemical and mechanical impacts of muscle contraction in this setting, motivates investigating this phenomenon in vitro. This study demonstrates that tuning the mechanical properties of fibrin enables longitudinal culture of highly contractile skeletal muscle monolayers, enabling functional characterization of and long‐term secretome harvesting from exercised tissues. Motor neurons stimulated with exercised muscle‐secreted factors significantly upregulate neurite outgrowth and migration, with an effect size dependent on muscle contraction intensity. Actuating magnetic microparticles embedded within fibrin hydrogels enable dynamically stretching motor neurons and non‐invasively mimicking the mechanical effects of muscle contraction. Interestingly, axonogenesis is similarly upregulated in both mechanically and biochemically stimulated motor neurons, but RNA sequencing reveals different transcriptomic signatures between groups, with biochemical stimulation having a greater impact on cell signaling related to axonogenesis and synapse maturation. This study leverages actuating extracellular matrices to robustly validate a previously hypothesized role for muscle contraction in regulating motor neuron growth and maturation from the bottom‐up through both mechanical and biochemical signaling. 

Leveraging living muscle as an efficient and adaptive actuator for soft robots has been of increasing interest over the past decade, with a focus on proof‐of‐concept demonstrations of function. Reproducible design and scalable manufacturing of biohybrid machines requires methods to increase the stroke output of strain‐limited muscle actuators and enable accurate and precise quality control and performance monitoring. Compliant mechanical elements, termed flexures, are designed to enhance muscle contractile stroke to ≈5× previously reported values and decode contraction dynamics with high spatiotemporal resolution. Combining rigid and flexible elements within a linear elastic flexure enables us to outperform the sensitivity of gold standard elastomeric beam‐based measurements of muscle contraction at both low‐ and high‐frequency stimulations. Flexures are leveraged to make quantitative comparisons of force, work, and power outputs in muscle actuators, driving us to discover a new observation of frequency‐dependent fatigue in muscle, and also develop a novel method for tuning muscle contractile dynamics in a frequency‐independent manner. By enhancing the contractile stroke of muscle actuators and precisely tuning contractile dynamics and endurance with unprecedented precision, this study sets the stage for leveraging flexures to improve robust, reproducible, and predictive design and manufacturing of next‐generation biohybrid robots.