Journal
JOURNAL OF APPLIED PHYSIOLOGY
Volume 126, Issue 5, Pages 1474-1482Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/japplphysiol.00865.2018
Keywords
active tension; chaperones; mechanosensing; passive tension; phosphorylation
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Funding
- European Union
- Federal Ministry for Education and Research (ERA-Net, MINOTAUR)
- German Research Foundation [SFB 1002, TP A08]
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Titin has long been recognized as a mechanical protein in muscle cells that has a main function as a molecular spring in the contractile units, the sarcomeres. Recent work suggests that the titin spring contributes to muscle contraction in a more active manner than previously thought. In this review, we highlight this property, specifically the ability of the immunoglobulin-like (Ig) domains of titin to undergo unfolding-refolding transitions when isolated titin molecules or skeletal myofibrils are held at physiological force levels. Folding of titin Ig domains under force is a hitherto unappreciated, putative source of work production in muscle cells, which could work in synergy with the actomyosin system to maximize the energy delivered by a stretched, actively contracting muscle. This review also focuses on the mechanisms shown to modulate titin-based viscoelastic forces in skeletal muscle cells, including chaperone binding, titin oxidation, phosphorylation, Ca2+ binding, and interaction with actin filaments. Along the way, we discuss which of these modulatory mechanisms might contribute to the phenomenon of residual force enhancement relevant for eccentric muscle contractions. Finally, a brief perspective is added on the potential for the alterations in titin-based force to dynamically alter mechano-chemical signaling pathways in the muscle cell. We conclude that titin from skeletal muscle is a determinant of both passive and active tension and a bona fide mechanosensor, whose stiffness is tuned by various independent mechanisms.
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