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

Rationale: Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique ␤-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 cardiomechanosensing. 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. 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 cross-links via ␣-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 proapoptotic 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 that 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 that may also play a role in human heart failure. T he heart is a dynamic organ capable of self-adaptation to mechanical demands, but the underlying molecular mechanisms remain poorly understood. We have previously shown that the sarcomeric Z-disk, which serves as an important anchorage site for titin and actin molecules, not only is important for mechanical force transduction but also harbors a pivotal mechanosensitive signalosome in which muscle LIM protein (MLP) and telethonin play major roles in the perception of mechanical stimuli. 1–3 Here we focus on tele-thonin, a striated-muscle-specific protein with a unique ␤-sheet structure (and no direct homologue genes), enabling it to bind in an antiparallel (2:1) sandwich complex to the titin Z1-Z2 domains, essentially " gluing " together the N-termini of 2 adjacent titin molecules. 4 Interestingly, the telethonin– titin interaction represents …