New insights into the structural roles of nebulin in skeletal muscle

Abstract

One important feature of muscle structure and function that has remained relatively obscure is the mechanism that regulates 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. Another structural feature of skeletal muscle that is not well understood is the mechanism involved in maintaining the regular lateral alignment of adjacent sarcomeres, that is, myofibrillar connectivity. Recent studies indicate that nebulin is part of a protein complex that mechanically links adjacent myofibrils. Thus, novel structural roles of nebulin in skeletal muscle involve the regulation of thin filament length and maintaining myofibrillar connectivity. When these functions of nebulin are absent, muscle weakness ensues, as is the case in patients with nemaline myopathy with mutations in nebulin. Here we review these new insights in the role of nebulin in skeletal muscle structure.

Figure 1

(a) Schematic of the structural organization of skeletal muscle (top) and sarcomere (bottom). (b) Schematic of the human nebulin sequence. Nebulin has a highly modular structure, with, in the central region, (M9–M162) seven modular repeats arranged into twenty-two superrepeats (only two of which are shown).

Figure 2

(a) Schematic illustrating the range of thin filament lengths found in nebulin-deficient muscle fibers. Immunoelectron microscopy [14] showed that thin filament lengths in wildtype tibialis cranialis muscle are a constant 1.2 μm, but in nebulin-deficient muscle are on average ~0.8 μm and range from ~0.4 to 1.2 μm. (b) The force-sarcomere length relation of murine wt muscle fibers has a characteristic force plateau followed by a descending limb. The force-sarcomere length relation of nebulin-deficient fibers is shifted leftward compared to wt fibers, and the force plateau is absent. (c) Similarly, the force-sarcomere length relation of nebulin-deficient human muscle fibers (dissected from biopsies obtained from patients with nemaline myopathy) is shifted to the left, and the force plateau is absent as well [16].

Figure 3

(a) Wildtype fibers have a regular structure with well-aligned sarcomeres. In nebulin-deficient fibers sarcomeres are misaligned and the Z-disk are out of register. Arrows indicate how Z-disk displacement (ΔX) was defined. (b) Z-disk displacement is significantly increased in nebulin-deficient fibers. (modified from Tonino et al. [27]).