I-Band Titin Interaction with Myosin in the Muscle Sarcomere during Eccentric Contraction: The Titin Entanglement Hypothesis

Abstract

The mechanisms underlying muscle contraction have largely been defined within a two filament, actin and myosin based model. The discovery of a third filament decades later called titin, has yet to be adequately incorporated into contemporary thinking, despite mounting evidence for the significance of this molecular spring. Upon muscle stretch, this titin spring works to restore muscles to their resting length by developing a passive force. The magnitude of this passive force can be quite variable due to titin's dynamic nature, but one of the most significant changes to force development may arise from a reversible titin truncation through transient binding to neighboring actin filaments. When titin was fluorescently labelled within the muscle myofibril, segments of I-band titin were tracked during passive and active stretch in order to evaluate a titin-actin interaction. Interestingly, a titin-actin binding was not observed, but unexpectedly, a titin-myosin entanglement ensued whereby parts of I-band titin overlapped spatially with myosin filaments. When muscles were activated, the distal Ig and part of the PEVK region became firmly anchored to the myosin thick filament, while the proximal Ig and PEVK regions were forced to elongate dramatically to accommodate the muscle lengthening. This pattern remained until a threshold stress was achieved, after which point titin was rapidly freed from myosin, and the elongation pattern reversed. After this threshold, the pattern of active titin elongation resembled that of the passive titin elongation. This previously unimagined mechanism has the potential to explain some of the departures from theory that the two filament model cannot, and may have great implications for muscle contraction.