Telethonin Deficiency Is Associated With Maladaptation to Biomechanical Stress in the Mammalian Heart

Abstract

Rationale Telethonin (also known as titin-cap or t-cap) is a 19 kDa Z-disk protein with a unique β-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardio-mechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin’s in vivo function. Objective Here we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of its mutation. Methods and Results By using a variety of different genetically altered animal models and biophysical experiments we show that, contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin crosslinks via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the pro-apoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis (“mechanoptosis”). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect which may contribute to enhanced rates of apoptosis found in these hearts. Conclusions Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect which may also play a role in human heart failure.

High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice

“…In the heart, 447 genes were differentially expressed in mice fed a high-fiber diet (FDR <0.05; Table IV in the online-only Data Supplement), and 536 genes were differentially expressed in mice that received acetate (Table V in the online-only Data Supplement) compared with those fed the control diet. One hundred ninetytwo genes were in common between high fiber and acetate ( Figure 6C and 6D) such as the upregulation of genes thought to have a preventive role for heart disease such as titin-cap (Tcap) 27 and tissue metallopeptidase inhibitor 4 (Timp4). 28 It is interesting to note that in both the kidney and heart, fiber and acetate downregulated the gene for early growth response protein 1 (Egr1) mRNA ( Figure 6D), a master regulator of cardiovascular pathology.…”

The sarcomeric cytoskeleton: from molecules to motion

“…These data suggested that telethonin was required for the structural integrity of sarcomeres and titin-regulated sarcomere assembly (Gregorio et al, 1998;Mues et al, 1998). However, recent studies in myocytes (Wang et al, 2005) and animal models revealed that telethonin enters the Z-disk late and is therefore not involved in primary myofibril assembly (Zhang et al, 2009) or required to maintain sarcomere integrity under baseline conditions (Knoll et al, 2011). Rather, it appears that, at least in cardiomyocytes, the titintelethonin complex is somehow implicated in the organisation or maintenance of T-tubules near the Z-disk (Fig.…”

Gigantic Business

“…31,34,35 The well-documented strong binding of telethonin to the Ig1/Ig2 domains 33 is not crucial for anchoring titin firmly to the Z-disk. 36 Telethonin interacts, among others, with the E3 ubiquitin ligase mouse-double-minute-2-homolog, 37 which links Z-disk titin to the ubiquitin-proteasomal degradation pathway (Figure 3). Interactions with nebulin/nebulette 38 and filamin-C 39 connect the first unique sequence at titin's NH 2 terminus to other components of the intra-and extrasarcomeric cytoskeleton ( Figure 2B), providing additional structural stability.…”