The contractile machinery of heart and skeletal muscles has as an essential component
the thick filament, comprised of the molecular motor myosin. The thick filament is
of a precisely controlled length, defining thereby the force level that muscles generate
and how this force varies with muscle length. It has been speculated that the mechanism
by which thick filament length is controlled involves the giant protein titin, but
no conclusive support for this hypothesis exists. Here we show that in a mouse model
in which we deleted two of titin's C-zone super-repeats, thick filament length is
reduced in cardiac and skeletal muscles. In addition, functional studies reveal reduced
force generation and a dilated cardiomyopathy (DCM) phenotype. Thus, regulation of
thick filament length depends on titin and is critical for maintaining muscle health.
