Skeletal muscles drive voluntary movements. Striated muscles allow fish to swim, birds to fly and our heart to beat. Skeletal muscles are built of multiple fascicles, which are bundles containing many muscle fibers. Looking at these structures under a microscope, smaller structures of muscle fibers, so-called myofibrils, become visible. These structures are highly organized and show regular patterns of specific units. These specific periodic subunits are the sarcomeres.
Sarcomeres self-assemble as the smallest unit of skeletal muscles. Mature sarcomeres are crystal-like structures with a specific size of 2-3 micrometer. Sarcomeres are bounded by the so-called Z-disc, which contains more than thirty different proteins. Polar actin filaments are cross-linked to the Z-disc. Myosin motor filaments are anchored, facing the center of the sarcomere. The giant protein titin links myosin and actin filaments and stabilizes the sarcomere. Sarcomeres shorten in length during muscle contraction, by relative sliding of myosin through actin filaments. The myosin motor filaments walk through the polar actin filament, under energy conversion. While this sliding mechanism is known, it is unclear how sarcomeres form during the multi-stage developmental process of skeletal muscles.
How to build a sarcomere? Despite many years of research, it is poorly understood how sarcomeres self-assemble into regular patterns. In this context, the main questions are: which sarcomere components regularly align first, and how are actin filaments orientated with the correct polarity? To answer these questions, we observe early stages of myofibrillogenesis in the fruit fly Drosophila melanogaster and quantify the regular alignment of selected proteins using a new algorithm.
Our result:
Data of early stages of myofibrillogenesis display a temporal order during sarcomere assembly. Myosin, titin (Sallimus in fruit fly) and the Z-disc proteins alpha-actinin pattern first, while actin filaments only follow later. With these experimental observations, we postulate a new theoretical framework of sarcomere assembly. We establish a minimal mathematical model, including possible molecular interactions between myosin and Z-disc proteins. In particular, we show that a non-local interaction with the protein titin is sufficient to drive the pattern formation process. With this non-local interaction, we take into account that myosin and titin are extended filaments of a specific size, setting the sarcomere length. With agent-based simulations we demonstrate that the model is robust to stochastic small number fluctuations. In addition, it is known that mechanical tension is induced during myofibrillogenesis. Local tension, produced by myosin motor activity can guide the assembly of sarcomeres, too. Thus, we formulate a second minimal mathematical model accounting for local tension. Specifically, we set the focus on the non-covalent binding of alpha-actinin (catch-bond behavior). In the presence of local tension, the lifetime of alpha-actinin increases. We demonstrate for this second model that such an alternative non-local interaction can give rise to periodic patterns of a specific length under presence of mechanical tension, even though it is less robust. We discuss similarities and differences of both models and propose the possibility that myofibrillogenesis in biological systems is a combination of both models.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89186 |
| Date | 07 February 2024 |
| Creators | Kolley, Francine |
| Contributors | Friedrich, Benjamin M., Schießel, Helmut, Grill, Stephan W., Technische Universität Dresden |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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