Titin extension explains residual force enhancement in skeletal muscle.

Authors

Christopher Tiessen, Armaan Sekhon, Dhairya Desai, Tim Leonard, Fatima Abu Shagra, Samhar Samer Alouch, Walter Herzog

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 41. Pages e2534671123. Oct 13, 2026. Epub Oct 06, 2026.

Abstract

Residual force enhancement (RFE) is an inherent property of mammalian skeletal muscle. After eccentric stretch, muscle produces increased steady-state force compared to purely isometric contraction at the same sarcomere length and activation level. This property has been known for over 70 y and yet remains largely unexplained. Titin, a giant spring-like protein responsible for passive force generation and stabilization of the sarcomere, has been suggested as a potential candidate for causing RFE. To test whether titin may be responsible for RFE, we used multiple titin immunolabels on single isolated myofibrils to approximately track the migration of individual titin segments in real-time. In comparison to many previous attempts to label titin in sarcomeres, our labeling using N2A and distal PEVK labels did not impact mechanical properties of the myofibril and thus permitted accurate tracking of titin segments within single sarcomeres. We found the approximate length of titin's PEVK segment was significantly longer in RFE compared to isometric control activations at similar final sarcomere lengths, indicating increased force on titin filaments in RFE. Using a modified worm-like chain model, we predict titin-associated force contributes up to 62% of increased force during RFE. Additionally, using a continuous eccentric stretch protocol, we provide indirect evidence suggesting titin-actin interactions may be responsible for increased force on titin during RFE. To date, this represents one of the most convincing pieces of evidence suggesting that titin is responsible for RFE. Thus, our data indirectly support the proposed "three-filament model" where muscle activation induces cross-bridge interactions and titin-actin interactions.

PMID:
42837457
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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