Use of animal models to understand titin physiology and pathology

Abstract

In recent years, increasing attention has been paid to titin ( TTN ) and its mutations. Heterozygous TTN truncating variants (TTNtv) increase the risk of a cardiomyopathy. At the same time, TTNtv and few missense variants have been identified in patients with mainly recessive skeletal muscle diseases. The pathogenic mechanisms underlying titin‐related diseases are still partly unknown. Similarly, the titin mechanical and functional role in the muscle contraction are far from being exhaustively clarified. In the last few years, several animal models carrying variants in the titin gene have been developed and characterized to study the structural and mechanical properties of specific titin domains or to mimic patients' mutations. This review describes the main animal models so far characterized, including eight mice models and three fish models (Medaka and Zebrafish) and discusses the useful insights provided by a thorough characterization of the cell‐, tissue‐ and organism‐phenotypes in these models.

Combinatorial extracellular matrix cues with mechanical strain induce differential effects on myogenesis in vitro

“… 34 Additionally, cluster B corresponded to genes upregulated on either single-factor ECMs under static condition, containing genes such Ttn and Tnnt1 , which are responsible for muscle contraction in sarcomeres. 35 These findings suggest that sarcomeric genes were distinctively different on the C + F + L combination, compared to the single factor components.…”

Titin: roles in cardiac function and diseases

“…A large proportion of cardiac titin expresses all six exons, Mex1-Mex6, unlike skeletal muscle, which often lacks Mex5 ( Kolmerer et al, 1996 ). If Mex5 is not expressed in cardiac tissue, pathogenic phenotypes often develop ( Marcello et al, 2022 ). Mex 1 encodes the titin kinase (TK), which is responsible for binding multiple different proteins ( Kolmerer et al, 1996 ; Puchner et al, 2008 ).…”

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

“…Several mouse models carrying variants in the TTN gene have been developed to understand the structural role of TTN and the clinical correlates in patients. All of the available animal models have been excellently summarized by Marcello and colleagues in a very recent review exclusively focused on TTN pathophysiology [ 152 ].…”