The sarcomeric cytoskeleton: from molecules to motion

Abstract

Highly ordered organisation of striated muscle is the prerequisite for the fast and unidirectional development of force and motion during heart and skeletal muscle contraction. A group of proteins, summarised as the sarcomeric cytoskeleton, is essential for the ordered assembly of actin and myosin filaments into sarcomeres, by combining architectural, mechanical and signalling functions. This review discusses recent cell biological, biophysical and structural insight into the regulated assembly of sarcomeric cytoskeleton proteins and their roles in dissipating mechanical forces in order to maintain sarcomere integrity during passive extension and active contraction. α-Actinin crosslinks in the Z-disk show a pivot-and-rod structure that anchors both titin and actin filaments. In contrast, the myosin crosslinks formed by myomesin in the M-band are of a balland-spring type and may be crucial in providing stable yet elastic connections during active contractions, especially eccentric exercise.

α-Actinin/titin interaction: A dynamic and mechanically stable cluster of bonds in the muscle Z-disk

“…Apart from a direct interaction between actin filaments and titin at the Z-disk edge (13), the most prominent candidate for the anchoring of titin within the Z-disk is its interaction with α-actinin (Fig. 1B) (6,12,14).Four isoforms of human α-actinin have been identified: the calcium-insensitive muscle isoforms 2 and 3, which cross-link actin filaments in sarcomere-delimiting Z-disk complexes, and calcium-sensitive nonmuscle isoforms 1 and 4. α-Actinin is an antiparallel homodimer whose most prominent task is crosslinking actin filaments of neighboring sarcomeres in the Z-disk ( Fig. 1B; reviewed in ref.…”

“…Apart from a direct interaction between actin filaments and titin at the Z-disk edge (13), the most prominent candidate for the anchoring of titin within the Z-disk is its interaction with α-actinin (Fig. 1B) (6,12,14).…”

“…1B; reviewed in ref. 14). In each subunit, a flexible region called the neck separates the actin binding domain (ABD) from four spectrin-like repeats (SR) forming the rod region (Fig.…”

Novel myosin-based therapies for congenital cardiac and skeletal myopathies

“…Subsequently, when calcium ions are removed from the cytoplasm, the sarcomere relaxes. Other sarcomeric proteins such as titin, the intermediate filaments and Z-disc proteins are also important for mechanosensing and maintaining the sarcomeric structure during contraction 15 16. When sarcomeric mutations occur, the genotype-phenotype relationships become complex.…”

Binding of Myomesin to Obscurin-Like-1 at the Muscle M-Band Provides a Strategy for Isoform-Specific Mechanical Protection

“…This fundamental activity requires the correct positioning of hundreds of proteins assembled in an overall functional architecture that need to respond to mechanical force in a cooperative, orchestrated way, as well as providing key integration of regulatory signals. The Z-disc and M-band sarcomeric regions (Figure 1A), although not directly involved in the actomyosin complex, are hubs where multiple structural and regulatory proteins are linked (Gautel and Djinovic-Carugo, 2016). In particular, the central M-band, where titin filaments entering from opposite half-sarcomeres overlap, has been proposed as a structural safeguard of sarcomere integrity during force-generation cycles (Agarkova et al., 2003).…”