Titin Hysteresis is Greater for Actively Lengthened Compared to Passively Lengthened Skeletal Muscle Sarcomeres

Titin is a giant protein found in skeletal muscle which behaves mechanically like a molecular spring. The extensible region of titin within the sarcomere contains spring-like domains arranged in series with stiffness and visco-elastic properties which come into play in an orderly fashion with increasing sarcomere length. When lengthened within the physiologically relevant range of sarcomere excursion, first the Ig domains align, followed by stretching of the PEVK region. Beyond the physiological range, Ig domains unfold, and this unfolding is thought to be highly visco-elastic.Active muscle lengthened from 1.8 to 4.0µm and to beyond myofilament overlap (> 4.0µm) will produce more force than passively lengthened muscle at the same sarcomere length [1]. Higher force beyond 4µm is expected to increase the hysteresis of titin by increasing Ig domain unfolding.Rabbit psoas myofibrils were used for these experiments. Single myofibrils with an initial mean sarcomere length (SL) of 2.8µm were activated with Ca+2 and ATP (no Ca+2 for passive) and lengthened to approximately 4.5µm and then immediately cycled (10x) ±0.25µm. Mean 1st peak force was higher in active (n=6) versus passive (n=5) at 338.9±137.2nN/µm2 versus 103.2±17.2nN/µm2, as expected. Mean peak force fell continuously from the 1st to the 10th cycle in active, while the peak force stabilized in passive tests by the 4th cycle. Hysteresis was greater in the active tests; mean 1st cycle hysteresis was 10.8±5.4nN·µm versus 1.3±0.9nN·µm. We conclude that the higher forces observed at all SL for active compared to passive lengthening results in increased visco-elastic behaviour in titin through increased Ig domain unfolding and this unfolding is not completed in active tests even after 10 repeated stretch-shortening cycles at long SL.[1] Leonard and Herzog, 2010, AJP-(Cell) 299:14-20.