Titin Gene and Protein Functions in Passive and Active Muscle

Abstract

The thin and thick filaments of muscle sarcomeres are interconnected by the giant protein titin, which is a scaffolding filament, signaling platform, and provider of passive tension and elasticity in myocytes. This review summarizes recent insight into the mechanisms behind how titin gene mutations cause hereditary cardiomyopathy and how titin protein is mechanically active in skeletal and cardiac myocytes. A main theme is the evolving role of titin as a modulator of contraction. Topics include strain-sensing via titin in the sarcomeric A-band as the basis for length-dependent activation, titin elastic recoil and refolding of titin domains as an energy source, and Ca-dependent stiffening of titin stretched during eccentric muscle contractions. Findings suggest that titin stiffness is a principal regulator of the contractile behavior of striated muscle. Physiological or pathological changes to titin stiffness therefore affect contractility. Taken together, titin emerges as a linker element between passive and active myocyte properties.

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

“…B,C). Interestingly, Ig unfolding provides a mechanism to store elastic energy, which is released by refolding , potentially assisting active muscle contraction (titin's role in active muscle contraction is discussed in detail in reference ). In conclusion, reversible Ig domain unfolding is a physiologically relevant mechanism of titin extension‐release and sarcomeric force adjustment.…”

“…Since titin stiffness is a main contributor to cardiomyocyte stiffness and thus, total myocardial stiffness , the modulation of titin stiffness will affect the wall tension of the heart chambers, with consequences for diastolic filling and subsequent systolic pump function (via an autoregulatory mechanism known as the Frank–Starling law) . One important long‐term mechanism of titin stiffness adjustment is titin isoform switching.…”

“…Among other things, these changes will alter downstream signaling events, including titin phosphorylation. This could become critical to overall cardiac function, if the changes in titin‐based stiffness become substantial: if myocardial stiffness becomes too high, ventricular filling will be compromised, whereas lower than normal stiffness will blunt length‐dependent activation and thus, impair the Frank–Starling response .…”

“…Titin generates ‘passive’ tension through its spring‐like characteristics , which determine—along with those of the microtubular network —the ‘passive’ stiffness of the cardiomyocyte and contribute a significant proportion of the total myocardial wall stiffness . Moreover, titin stiffness and titin interactions with other myofilament proteins can modulate Ca 2+ ‐dependent active tension . Therefore, alterations in titin‐based spring force affect both the passive and the active forces of cardiomyocytes.…”

A new long-read RNA-seq analysis approach identifies and quantifies novel transcripts of very large genes

“…Titin spans half the sarcomere in length, and is coded by transcripts up to ~106 kilobases long, with 363 exons (Bang et al 2001). Titin primarily functions as a molecular spring that helps maintain the sarcomere as muscle cells contract (Linke 2017). The elasticity of muscle cells depends on differential splicing of the titin transcript coding a highly repetitive PEVK region, and repeating units of immunoglobulin (Ig), and fibronectin-type-3 domains (Linke 2017).…”