Nature's Journal Club

Michelle Peckham

University of Leeds, UK

A cell biologist ponders an outstanding mystery in muscle formation.

Heart and skeletal muscles have a beautiful, almost crystalline structure of repeating contractile units called sarcomeres. The length of these units is precisely regulated along with the lengths of two types of overlapping filament (thick and thin) that they contain. Muscles contract when crossbridges from thick filaments interact with actin in thin filaments. The amount of contraction depends on the length of each filament and how much they overlap.

A thick filament contains exactly 294 myosin molecules — a limit imposed by the giant ‘ruler’ protein titin. Yet it is not clear what regulates the length of thin filaments. The protein nebulin has been a key candidate: its size corresponds to thin filament length in several species. Puzzlingly, however, in mice with a targeted deletion of nebulin, skeletal muscle thin filaments are the right length, at least at birth. And Ryan Littlefield at the University of Washington in Friday Harbor and his colleagues have now shown that nebulin is too short to be the ruler — its end is located just short of the tips of the thin filaments (A. Castillo et al. Biophys. J. 96, 1856–1865; 2009).

Because of the way in which thick filaments are built, their middles — at the centre of the sarcomere — have no crossbridges. Littlefield and his colleagues suggest that thin filaments, which grow towards the middle of sarcomeres from their edges, stop growing when they reach this ‘bare’ zone. Intriguingly, this paper also shows that thin filament lengths in different muscles correspond to the length of titin in those muscles. A single titin molecule stretches from the edge to the middle of the sarcomere. If titin modulates overall sarcomere length, and thus the distance to the bare zone in the centre of the sarcomere, this could indirectly regulate thin filament lengths. Maybe the biggest protein known has yet another job.

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