Telethonin-deficiency initially presenting as a congenital muscular dystrophy

BioMed Research International

Buyandelger

Lab

2011

108

104

The sarcomeric Z-disc defines the lateral borders of the sarcomere and has primarily been seen as a structure important for mechanical stability. This view has changed dramatically within the last one or two decades. A multitude of novel Z-disc proteins and their interacting partners have been identified, which has led to the identification of additional functions and which have now been assigned to this structure. This includes its importance for intracellular signalling, for mechanosensation and mechanotransduction in particular, an emerging importance for protein turnover and autophagy, as well as its molecular links to the t-tubular system and the sarcoplasmic reticulum. Moreover, the discovery of mutations in a wide variety of Z-disc proteins, which lead to perturbations of several of the above-mentioned systems, gives rise to a diverse group of diseases which can be termed Z-discopathies. This paper provides a brief overview of these novel aspects as well as points to future research directions.

Section: Z-disc-related Proteinsmentioning

confidence: 99%

The Sarcomeric Z‐Disc and Z‐Discopathies

BioMed Research International

Buyandelger

Lab

2011

108

104

“…11–14 In addition, telethonin was shown to interact with MDM2 15 and MuRF1 16 - E3 ubiquitin ligases with strong impact on cardiac protein turnover as well as with the proapoptotic protein Siva 17 . Recessive nonsense mutations in the telethonin gene are associated with limb-girdle muscular dystrophy type 2 G 18–20 and heterozygous missense mutations with dilated and hypertrophic forms of cardiomyopathy 1, 21–22 as well as with intestinal pseudo-obstruction. 23 Interestingly, a naturally occurring telethonin variant that has a Glu13 deletion (E13del telethonin) was initially found in patients affected by hypertrophic cardiomyopathy 21 and then later in healthy, unaffected individuals.…”

Section: Introductionmentioning

confidence: 99%

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

Linke

Zou

et al. 2011

Circulation Research

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.

“…A variety of telethonin mutations are associated with the development of congenital diseases, including limb girdle muscular dystrophy 2G [8, 35, 38], hypertrophic cardiomyopathy (HCM), DCM [4, 12, 18], and intestinal pseudo-obstruction [32]. …”

Section: Sarcomere-related Mechanisms Of Mechanosensationmentioning

confidence: 99%

Mechano-signaling in heart failure

Buyandelger

Mansfield

Pflugers Arch - Eur J Physiol

2014

Mechanosensation and mechanotransduction are fundamental aspects of biology, but the link between physical stimuli and biological responses remains not well understood. The perception of mechanical stimuli, their conversion into biochemical signals, and the transmission of these signals are particularly important for dynamic organs such as the heart. Various concepts have been introduced to explain mechanosensation at the molecular level, including effects on signalosomes, tensegrity, or direct activation (or inactivation) of enzymes. Striated muscles, including cardiac myocytes, differ from other cells in that they contain sarcomeres which are essential for the generation of forces and which play additional roles in mechanosensation. The majority of cardiomyopathy causing candidate genes encode structural proteins among which titin probably is the most important one. Due to its elastic elements, titin is a length sensor and also plays a role as a tension sensor (i.e., stress sensation). The recent discovery of titin mutations being a major cause of dilated cardiomyopathy (DCM) also underpins the importance of mechanosensation and mechanotransduction in the pathogenesis of heart failure. Here, we focus on sarcomere-related mechanisms, discuss recent findings, and provide a link to cardiomyopathy and associated heart failure.