Abstract
The sliding filament model of the sarcomere was developed more than half a century ago. This model, consisting only of thin and thick filaments, has been successful in explaining many, but not all, features of skeletal muscle. Work during the 1980s revealed the existence of two additional filaments: the giant filamentous proteins titin and nebulin. Whereas the role of titin rapidly progressed, nebulin’s role in muscle structure and function remained long nebulous. An important feature of muscle structure and function that has remained relatively obscure concerns the mechanisms that are involved in regulating thin filament length. Filament length is an important aspect of muscle function as force production is proportional to the amount of overlap between thick and thin filaments. Recent advances, due in part to the generation of nebulin KO models, reveal that nebulin plays an important role in the regulation of thin filament length, most likely by stabilizing F-actin assemblies. Another structural feature of skeletal muscle that has been incompletely understood concerns the mechanisms involved in maintaining Z-disk structure and the regular lateral alignment of adjacent sarcomeres during contraction. Recent studies indicate that nebulin is part of a protein complex that mechanically links adjacent myofibrils. In addition to these structural roles in support of myofibrillar force generation, nebulin has been also shown to regulate directly muscle contraction at the level of individual crossbridges: cycling kinetics and the calcium sensitivity of force producing crossbridges is enhanced in the presence of nebulin. Thus, these recent data all point to nebulin being important for muscle force optimization. Consequently, muscle weakness as the lead symptom develops in the case of patients with nemaline myopathy that have mutations in the nebulin gene. Here, we discuss these important novel insights into the role of nebulin in skeletal muscle function.
Highlights
NEBULIN IS INVOLVED IN SPECIFYING THIN FILAMENT LENGTH Skeletal muscle produces efficient contractile force because they contain thin and thick filaments of well-defined lengths that are organized into regular, symmetric arrays that interdigitate
Since length is not an intrinsic property of actin filaments (actin monomers assemble in vitro to highly variable polymer lengths (Pollard and Borisy, 2003), thin filament length is likely to be specified in vivo by an actin-binding protein; for this, nebulin has been considered for a long time a prime candidate (Wang and Wright, 1988; Labeit et al, 1991; Labeit and Kolmerer, 1995), but critical evidence has been lacking up until recently
Immuno-electron microscopy revealed that a single nebulin molecule spans the thin filament with its C-terminus anchored at the Z-disk and its N-terminal region directed toward the thin filament pointed-end
Summary
NEBULIN IS INVOLVED IN SPECIFYING THIN FILAMENT LENGTH Skeletal muscle produces efficient contractile force because they contain thin and thick filaments of well-defined lengths that are organized into regular, symmetric arrays that interdigitate. The first work on these models revealed that in nebulin-deficient skeletal muscle the thin filaments are on average shorter, supporting a role for nebulin in the in vivo regulation of thin filament length (Bang et al, 2006; Witt et al, 2006).
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