For the past half century, the sliding filament-based cross-bridge theory has been the cornerstone of our understanding of how muscles contract. According to this theory, active force can only occur if there is overlap between the contractile filaments, actin and myosin. Otherwise, forces are thought to be caused by passive structural elements and are assumed to vary solely because of the length of the muscle. We observed increases in muscle force by a factor of 3 to 4 above the purely passive forces for activated and stretched myofibrils in the absence of actin-myosin overlap. We show that this dramatic increase in force is crucially dependent on the presence of the structural protein titin, cannot be explained with calcium activation, and is regulated by actin-myosin-based cross-bridge forces before stretching. We conclude from these observations that titin is a strong regulator of muscle force and propose that this regulation is based on cross-bridge force-dependent titin-actin interactions. These results suggest a mechanism for stability of sarcomeres on the "inherently unstable" descending limb of the force-length relationship, and they further provide an explanation for the protection of muscles against stretch-induced muscle injuries.

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Residual force enhancement has been observed following active stretch of skeletal muscles and single fibres. However, there has been intense debate whether force enhancement is a sarcomeric property, or is associated with sarcomere length instability and the associated development of non-uniformities. Here, we studied force enhancement for the first time in isolated myofibrils (nZ18) that, owing to the strict in series arrangement, allowed for evaluation of this property in individual sarcomeres (nZ79). We found consistent force enhancement following stretch in all myofibrils and each sarcomere, and forces in the enhanced state typically exceeded the isometric forces on the plateau of the force-length relationship. Measurements were made on the plateau and the descending limb of the force-length relationship and revealed gross sarcomere length non-uniformities prior to and following active myofibril stretching, but in contrast to previous accounts, revealed that sarcomere lengths were perfectly stable under these experimental conditions. We conclude that force enhancement is a sarcomeric property that does not depend on sarcomere length instability, that force enhancement varies greatly for different sarcomeres within the same myofibril and that sarcomeres with vastly different amounts of actin-myosin overlap produce the same isometric steady-state forces. This last finding was not explained by differences in the amount of contractile proteins within sarcomeres, vastly different passive properties of individual sarcomeres or (half-) sarcomere length instabilities, suggesting that the basic mechanical properties of muscles, such as force enhancement, force depression and creep, which have traditionally been associated with sarcomere instabilities and the corresponding dynamic redistribution of sarcomere lengths, are not caused by such instabilities, but rather seem to be inherent properties of the mechanisms of contraction.

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Sarcomerogenesis, or the addition of sarcomeres in series within a fiber, has a profound impact on the performance of a muscle by increasing its contractile velocity and power. Sarcomerogenesis may provide a beneficial adaptation to prevent injury when a muscle consistently works at long lengths, accounting for the repeated-bout effect. The association between eccentric exercise, sarcomerogenesis and the repeated-bout effect has been proposed to depend on damage, where regeneration allows sarcomeres to work at shorter lengths for a given muscle-tendon unit length. To gain additional insight into this phenomenon, we measured fiber dynamics directly in the vastus lateralis (VL) muscle of rats during uphill and downhill walking, and we measured serial sarcomere number in the VL and vastus intermedius (VI) after chronic training on either a decline or incline grade. We found that the knee extensor muscles of uphill walking rats undergo repeated active concentric contractions, and therefore they suffer no contraction-induced injury. Conversely, the knee extensor muscles during downhill walking undergo repeated active eccentric contractions. Serial sarcomere numbers change differently for the uphill and downhill exercise groups, and for the VL and VI muscles. Short muscle lengths for uphill concentric-biased contractions result in a loss of serial sarcomeres, and long muscle lengths for downhill eccentric-biased contractions result in a gain of serial sarcomeres.