No abstract

Contractions on the descending limb of the total (active + passive) muscle force-length relationship (i. e. when muscle stiffness is negative) are expected to lead to vast half-sarco-mere-length inhomogeneities. This is however not observed in experiments-vast half-sarcomere-length inhomogeneities can be absent in myofibrils contracting in this range, and initial inhomogeneities can even decrease. Here we show that the absence of half-sar-comere-length inhomogeneities can be predicted when considering interactions of the semi-active protein titin with the actin filaments. Including a model of actin-titin interactions within a multi-scale continuum-mechanical model, we demonstrate that stability, accurate forces and nearly homogeneous half-sarcomere lengths can be obtained on the descending limb of the static total force-length relation. This could be a key to durable functioning of the muscle because large local stretches, that might harm, for example, the transverse-tubule system, are avoided. Author summary Muscle force generation is a complex process depending on muscle length, activation, and other time-dependent properties. Contractions on the descending limb of the force-length relation (i. e. when the maximum isometric force decreases with increasing muscle length) are interesting, since this behaviour is expected to result in non-physiological length inhomogeneities of the muscle microstructure. Previously, different mechanisms have been suggested that could have a stabilising effect on the muscle microstructure. However, superposition of several phenomena makes it difficult to separate the influence of a single mechanism in an experimental setup. Within a model, individual phenomena can be knocked out to quantify the influence of a single process. Here we show, using a PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi. physiologically motivated model of the whole muscle, that variable mechanical properties of the large protein titin (controlled by calcium as a second messenger) can guarantee stability of the muscle microstructure during contractions on the descending limb of the force-length relation.

The aim of the study was to investigate the time-dependent increase in the knee extensors' isometric strength as a response to voluntary, unilateral, isometric knee extension exercise (UIKEE). To do so, a systematic review was carried out to obtain data for a Bayesian longitudinal model-based meta-analysis (BLMBMA). For the systematic review, PubMed, Web of Science, SCOPUS, Chochrane Library were used as databases. The systematic review included only studies that reported on healthy, young individuals performing UIKEE. Studies utilizing a bilateral training protocol were excluded as the focus of this review lied on unilateral training. Out of the 3,870 studies, which were reviewed, 20 studies fulfilled the selected inclusion criteria. These 20 studies were included in the BLMBMA to investigate the time-dependent effects of UIKEE. If compared to the baseline strength of the trained limb, these data reveal that UKIEE can increase the isometric strength by up to 46%. A meta-analysis based on the last time-point of each available study was employed to support further investigations into UIKEE-induced strength increase. A sensitivity analysis showed that intensity of training (%MVC), fraction of male subjects and the average age of the subject had no significant influence on the strength gain. Convergence of BLMBMA revealed that the peak strength increase is reached after ~4 weeks of UIKEE training.

Homogenised finite-element (FE) skeletal muscle models provide a good trade-off between computational efficiency and physiological realism. This trade-off is in part due to the lack of explicit modelling of muscle fibres (MFs). As a consequence, the organisation of MFs into motor-unit territories (MUTs) is particularly challenging. The current paper presents a possible technique to adress this issue by assigning MUTs in a homogenised sense in terms of muscle volume to FE skeletal muscle models. This method allows control of inter-MUT distance, the amount of intermingling between MUTs and the order of MUT assignment. It was found that both assigning smaller MUTs first and allowing a moderate amount of intermingling significantly influence MUT distributions. This technique allows a simplified and straight-forward way to introduce MUTs into 3D FE skeletal muscle models.