Titin as a force-generating muscle protein under regulatory control

Area of Science:

• Muscle physiology
• Biophysics
• Molecular biology

Background:

• Titin is a large protein in muscle cells, primarily known for its role as a molecular spring within sarcomeres.
• Emerging research indicates titin's active contribution to muscle contraction, beyond its passive elastic properties.

Purpose of the Study:

• To review the active mechanical properties of titin, focusing on its immunoglobulin-like (Ig) domains.
• To explore mechanisms modulating titin's viscoelastic forces and their role in muscle function.
• To discuss titin's potential as a mechanosensor and its impact on cellular signaling.

Main Methods:

• Review of existing literature on titin's mechanical behavior.
• Analysis of studies investigating unfolding-refolding transitions in titin Ig domains under physiological force.
• Examination of modulatory mechanisms including chaperone binding, oxidation, phosphorylation, and Ca2+ binding.

Main Results:

• Titin's immunoglobulin-like domains undergo force-induced unfolding-refolding transitions at physiological forces.
• This process represents a potential source of work production, complementing the actomyosin system.
• Various mechanisms (chaperones, oxidation, phosphorylation, Ca2+ binding, actin interaction) modulate titin's force.

Conclusions:

• Titin is a key determinant of both passive and active tension in skeletal muscle.
• Titin functions as a mechanosensor, with its stiffness dynamically regulated by multiple mechanisms.
• Force-induced titin conformational changes may contribute to residual force enhancement during eccentric contractions.