Theory of sarcomere assembly inferred from sequential ordering of myofibril components

Abstract

Myofibrils in striated muscle cells are chains of regular cytoskeletal units termed sarcomeres, whose contractions drive voluntary movements of animals. Despite the well characterized order of the sarcomere components in mature sarcomeres, which explains the sarcomere contraction mechanism, the mechanism of molecular ordering during sarcomere assembly remains debated. Here, we put forward a theoretical framework for the self-assembly of sarcomeres. This theory is based on measurements of the sequential ordering of sarcomere components in developing Drosophila flight muscles, identified by applying a novel tracking-free algorithm: myosin, -actinin and the titin homologue Sallimus form periodic patterns before actin. Based on these results, we propose that myosin, Sallimus, and sarcomere Z-disc proteins including -actinin dynamically bind and unbind to an unordered bundle of actin filaments to establish an initial periodic pattern. As a consequence, periodicity of actin filaments is only established later. Our model proposes that non-local interactions between spatially extended myosin and titin/Sallimus containing complexes, and possibly tension-dependent feedback mediated by an -actinin catch-bond, drive this ordering process. We probe this hypothesis using mathematical models and derive predictive conditions for sarcomere pattern formation, guiding future experimental analysis.