An Active Role for Titin in Skeletal Muscle

Abstract

The sliding filament theory of muscle contraction is widely accepted as the means by which muscles generate active force. Recent studies have observed enhanced titin-based force in activated rabbit psoas myofibrils that were stretched to lengths which exceed filament overlap. These forces cannot be accounted for in the current theory, thus, alternative mechanisms of force production should be considered. Titin has been speculated to play a role in active force by binding to the thin filament, shortening and stiffening its spring length during skeletal muscle activation. To further investigate this, the present study uses a model (mdm) in which the titin protein is mutated. This study aims to test the hypothesis that the region of titin that binds to the thin filament during activation is contained within the mdm deletion in titin. If the deleted region of mdm titin modulates titin-based stiffness via activation-dependent binding to the thin filament, mdm would be deficient in this binding, resulting in a more compliant titin spring. To test this hypothesis, mouse psoas myofibrils were passively and actively stretched to ∼6.0 μm/sarcomere. When wild-type myofibrils were actively stretched to average sarcomere lengths that exceed filament overlap, force continued to increase and remained greater than the passive force at all lengths. This trend was not observed in mdm myofibrils. Actively stretched mdm myofibrils were more compliant than wild-type myofibrils and did not differ from passive wild-type or mdm myofibrils. An enhanced state of titin-based force has now been demonstrated in rabbit and mouse myofibrils, suggesting that modulation of titin force during activation may be an inherent property of skeletal muscle. This property is disrupted in mdm, suggesting that a critical function in the enhancement of titin-based force is lost in mdm titin.