Fluid flow in the sarcomere.

A highly organized and densely packed lattice of molecular machinery within the sarcomeres of muscle cells powers contraction. Although many of the proteins that drive contraction have been studied extensively, the mechanical impact of fluid shearing within the lattice of molecular machinery has received minimal attention. It was recently proposed that fluid flow augments substrate transport in the sarcomere, however, this analysis used analytical models of fluid flow in the molecular machinery that could not capture its full complexity. By building a finite element model of the sarcomere, we estimate the explicit flow field, and contrast it with analytical models. Our results demonstrate that viscous drag forces on sliding filaments are surprisingly small in contrast to the forces generated by single myosin molecular motors. This model also indicates that the energetic cost of fluid flow through viscous shearing with lattice proteins is likely minimal. The model also highlights a steep velocity gradient between sliding filaments and demonstrates that the maximal radial fluid velocity occurs near the tips of the filaments. To our knowledge, this is the first computational analysis of fluid flow within the highly structured sarcomere.

The Sliding Filament Theory Since Andrew Huxley: Multiscale and Multidisciplinary Muscle Research.

Two groundbreaking papers published in 1954 laid out the theory of the mechanism of muscle contraction based on force-generating interactions between myofilaments in the sarcomere that cause filaments to slide past one another during muscle contraction. The succeeding decades of research in muscle physiology have revealed a unifying interest: to understand the multiscale processes-from atom to organ-that govern muscle function. Such an understanding would have profound consequences for a vast array of applications, from developing new biomimetic technologies to treating heart disease. However, connecting structural and functional properties that are relevant at one spatiotemporal scale to those that are relevant at other scales remains a great challenge. Through a lens of multiscale dynamics, we review in this article current and historical research in muscle physiology sparked by the sliding filament theory.

In vivo X-ray diffraction and simultaneous EMG reveal the time course of myofilament lattice dilation and filament stretch.

Muscle function within an organism depends on the feedback between molecular and meter-scale processes. Although the motions of muscle's contractile machinery are well described in isolated preparations, only a handful of experiments have documented the kinematics of the lattice occurring when multi-scale interactions are fully intact. We used time-resolved X-ray diffraction to record the kinematics of the myofilament lattice within a normal operating context: the tethered flight of Manduca sexta As the primary flight muscles of M.sexta are synchronous, we used these results to reveal the timing of in vivo cross-bridge recruitment, which occurred 24 ms (s.d. 26) following activation. In addition, the thick filaments stretched an average of 0.75% (s.d. 0.32) and thin filaments stretched 1.11% (s.d. 0.65). In contrast to other in vivo preparations, lattice spacing changed an average of 2.72% (s.d. 1.47). Lattice dilation of this magnitude significantly affects shortening velocity and force generation, and filament stretching tunes force generation. While the kinematics were consistent within individual trials, there was extensive variation between trials. Using a mechanism-free machine learning model we searched for patterns within and across trials. Although lattice kinematics were predictable within trials, the model could not create predictions across trials. This indicates that the variability we see across trials may be explained by latent variables occurring in this naturally functioning system. The diverse kinematic combinations we documented mirror muscle's adaptability and may facilitate its robust function in unpredictable conditions.