Distinct roles for telethonin N‐versus C‐terminus in sarcomere assembly and maintenance

Sadikot, Takrima; Hammond, Courtney R.; Ferrari, Michael B.

doi:10.1002/dvdy.22263

Cited by 18 publications

(11 citation statements)

References 50 publications

(83 reference statements)

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“…In contrast to recently published zebrafish and xenopus knock down models 30–31 as well as what was expected based on the available knowledge, the analysis of myocardial function by echocardiography (online table I) as well as by in vivo heart catheterization using 3 – 4 months old telethonin −/− mice under basic conditions did not reveal any abnormal parameters. Histological analysis of the spontaneous cardiac phenotype of telethonin −/− mice revealed no alterations, including the amount of extracellular matrix deposition (fig.…”

Section: Resultscontrasting

confidence: 95%

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

Knöll

Linke

Zou

et al. 2011

Circulation Research

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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.

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Section: Resultscontrasting

confidence: 95%

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

Knöll

Linke

Zou

et al. 2011

Circulation Research

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“…To assess whether partial structural recovery at the subcellular level translated to improved physiological function, we conducted embryo locomotion (motility) assessments using a qualitative index-scoring matrix (Sadikot et al, 2010). Stage 34 embryos were scored on a scale of 0-5 for their response to an external stimulus (touching with forceps).…”

Section: Embryo Locomotion Is Improved Upon Rescue Of Tmod4 and Lmod3mentioning

confidence: 99%

“…Locomotion assays for embryonic muscle function. Embryos were assayed at st34 for locomotion using a qualitative index scale of 0-5 (Sadikot et al, 2010). (A) Embryos depleted of Tmod4 showed very little motility compared with control embryos.…”

Section: Tmod4 Is Essential For Skeletal Muscle Development and Locommentioning

confidence: 99%

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Leiomodin 3 and Tropomodulin 4 have overlapping functions during skeletal myofibrillogenesis

Nworu

Kraft

Schnurr

et al. 2014

Journal of Cell Science

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Precise regulation of thin filament length is essential for optimal force generation during muscle contraction. The thin filament capping protein tropomodulin (Tmod) contributes to thin filament length uniformity by regulating elongation and depolymerization at thin filament ends. The leiomodins (Lmod1-3) are structurally related to Tmod1-4 and also localize to actin filament pointed ends, but in vitro biochemical studies indicate that Lmods act instead as robust nucleators. Here, we examined the roles of Tmod4 and Lmod3 during Xenopus skeletal myofibrillogenesis. Loss of Tmod4 or Lmod3 resulted in severe disruption of sarcomere assembly and impaired embryonic movement. Remarkably, when Tmod4-deficient embryos were supplemented with additional Lmod3, and Lmod3-deficient embryos were supplemented with additional Tmod4, sarcomere assembly was rescued and embryonic locomotion improved. These results demonstrate for the first time that appropriate levels of both Tmod4 and Lmod3 are required for embryonic myofibrillogenesis and, unexpectedly, both proteins can function redundantly during in vivo skeletal muscle thin filament assembly. Furthermore, these studies demonstrate the value of Xenopus for the analysis of contractile protein function during de novo myofibril assembly.

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“…Point mutations inactivating the telethonin phosphorylation sites or short-term knockdown impair myofibril formation or maintenance in Xenopus [107]; in human, deletion of the C-terminal portion of telethonin [80] or mutations close to the TK phosphorylation site (R153H, [44]) cause hereditary limb-girdle muscular dystrophy (LGMD2G) or hypertrophic cardiomyopathy. This suggests an important yet uncharacterised function of the telethonin C-terminus in muscle maintenance.…”

Section: Substrates and Scaffoldsmentioning

confidence: 99%

Cytoskeletal protein kinases: titin and its relations in mechanosensing

Gautel

2011

Pflugers Arch - Eur J Physiol

118

120

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Titin, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein kinases. The most extensively studied member of this branch of the human kinome is the Ca2+–calmodulin (CaM)-regulated myosin light-chain kinases (MLCK). However, not all kinases of the MLCK branch are functional MLCKs, and about half lack a CaM binding site in their C-terminal autoinhibitory tail (AI). A unifying feature is their association with the cytoskeleton, mostly via actin and myosin filaments. Titin kinase, similar to its invertebrate analogue twitchin kinase and likely other “MLCKs”, is not Ca2+–calmodulin-activated. Recently, local protein unfolding of the C-terminal AI has emerged as a common mechanism in the activation of CaM kinases. Single-molecule data suggested that opening of the TK active site could also be achieved by mechanical unfolding of the AI. Mechanical modulation of catalytic activity might thus allow cytoskeletal signalling proteins to act as mechanosensors, creating feedback mechanisms between cytoskeletal tension and tension generation or cellular remodelling. Similar to other MLCK-like kinases like DRAK2 and DAPK1, TK is linked to protein turnover regulation via the autophagy/lysosomal system, suggesting the MLCK-like kinases have common functions beyond contraction regulation.

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Distinct roles for telethonin N‐versus C‐terminus in sarcomere assembly and maintenance

Cited by 18 publications

References 50 publications

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

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

Leiomodin 3 and Tropomodulin 4 have overlapping functions during skeletal myofibrillogenesis

Cytoskeletal protein kinases: titin and its relations in mechanosensing

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