The Giant Protein Titin Regulates the Length of the Striated Muscle Thick Filament-Titin Rules

Abstract

The contractile machinery of heart and skeletal muscles that powers life has as its most 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 the length of the thick filament is so exquisitely controlled involves the giant protein titin, but no conclusive support for or against exists. Here we show studies on a mouse model in which we deleted two of titin's C-zone super-repeats, located in the A-band region of the sarcomere. Structural studies using immunoelectron microscopy and super-resolution optical microscopy in both cardiac and skeletal muscles reveal a thick filament length that is reduced by ∼170 nm; functional studies reveal reduced force generation and a dilated cardiomyopathy (DCM) phenotype. Our studies show for the first time the important role of titin in regulating thick filament length, with each of titin's C-zone repeats being responsible for a quantal 43 nm thick filament length. We conclude that thick filament length regulation is titin-based and that this mechanism is crucial for maintaining muscle health.