Fig. 7

Proposed mechanism of force production in skeletal muscles including the “activation” of titin and its variable contribution to force production in skeletal muscles vis a vis the cross-bridge based actin-myosin based active forces. a Micrographs of serially arranged sarcomeres and a single sarcomere, plus schematic representation of a single sarcomere containing titin as the third filament besides actin and myosin. b Proposed mechanism of titin-based increase in force upon activation. Upon muscle activation, titin is thought to bind calcium, thereby increasing its inherent spring stiffness, and also to bind its proximal segment to actin, thereby shortening its free spring length and thus further increasing its stiffness. The left and right top figures indicate two different initial sarcomere lengths. Stretching the sarcomere passively to a given length will lead to the same passive force (centre) and titin is stretched without attaching to actin. Stretching the sarcomere actively to a given length (left and right bottom figures) will result in increased titin-based force because of calcium binding to titin and titin binding to actin, as explained in the text. Forces in the actively stretched sarcomere will depend on the initial length prior to the start of stretching, because titin is thought to attach at different points on actin, predicting that a longer stretch distance (bottom left figure) will result in a more increased force than a shorter stretch distance (bottom right figure). c Schematic illustration of the change in passive (titin-based) force between passive and active stretches of skeletal muscles. In the active stretch, the passive force starts at a shorter sarcomere (muscle) length, and passive force is stiffer than for the passive stretch because of the engagement of titin with actin and because of calcium binding to titin upon muscle activation. Note, how far the shift in passive force is, and how much stiffer the passive (titin-based) force is in actively compared to passively stretched muscle depends crucially on the initial sarcomere length and the amount of stretch. (Adapted from Herzog [14], with permission)