905). Longer thin filaments result in greater overlap with myosin thick filaments and thus the ability of a muscle to bear greater loads.
Distinct muscles have different biophysical properties and requirements, and the lengths of the many nebulin isoforms have been suggested to correlate with thin filament lengths in different muscles. Some attempts have been made to reduce nebulin function in culture, but what was really needed was a study in a living animal.
The team therefore used gene targeting to delete the nebulin gene in mice. Mutants were born in the expected numbers but ate little, thrived less, and died within days. Their muscles looked fine at birth but became disorganized with use, eventually forming messy aggregates that are also seen in humans with nebulin mutations.
Thin filaments in four muscles had almost identical lengths of ∼1 μm in the mutants. In wild type mice, by contrast, these same muscles had various different lengths—all longer than 1 μm. The researchers suggest that a nebulin-independent mechanism ensures that actin filaments in muscle reach the 1 μm mark. But nebulin must be present to guide further actin growth, perhaps by protecting the growing filament from capping proteins. They now plan to test this model by expressing specific nebulin isoforms in specific locations, to see if this is sufficient to determine different thin filament lengths.