Telomere shortening is a hallmark of genetic cardiomyopathies

Chang, Alex Chia Yu; Chang, Andrew Chia Hao; Kirillova, Anna; Sasagawa, Koki; Su, Willis; Weber, Gerhard; Lin, Jue; Termglinchan, Vittavat; Karakikes, Ioannis; Seeger, Timon; Dainis, Alexandra; Hinson, J. Travis; Seidman, Jonathan G.; Seidman, Christine E.; Day, John W.; Ashley, Euan A.; Wu, Joseph C.; Blau, Helen M.

doi:10.1073/pnas.1714538115

Cited by 58 publications

(85 citation statements)

References 30 publications

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“…Previously, studies have attributed the beneficial effects of clearance of senescent cells in murine ageing heart to other proliferation-competent cells and not CMs (Baker et al, 2016). Studies have also proposed a role for telomere shortening in CM senescence: Short telomeres have been observed in aged murine CMs (Rota et al, 2007) and in cardiomyocytes from individuals with end-stage hypertrophic or dilated cardiomyopathy (Chang et al, 2018) and mouse models of accelerated telomere shortening exhibit cardiac dysfunction (Chang et al, 2016). However, whether short telomeres per se are causal in cardiomyocyte senescence during natural ageing has not been determined.…”

Section: Discussionmentioning

confidence: 99%

Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

et al. 2019

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Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age‐related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post‐mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age‐related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent‐like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length‐independent telomere damage in cardiomyocytes activates the classical senescence‐inducing pathways, p21CIP and p16INK4a, and results in a non‐canonical senescence‐associated secretory phenotype, which is pro‐fibrotic and pro‐hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age‐related myocardial dysfunction and in the wider setting to ageing in post‐mitotic tissues.

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Section: Discussionmentioning

confidence: 99%

Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

et al. 2019

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“…Collectively, these data suggest that the airway epithelial cell telomere dysfunction is a molecular driver of CLAD pathology. Short telomeres are evident in diseases of tissue remodeling and fibrosis including skin dyskeratosis (26), hypertrophic cardiomyopathy (27)(28)(29), liver cirrhosis (30), Duchenne muscular dystrophy (31) , idiopathic pulmonary fibrosis (32), and CLAD (9). Telomere dysfunction secondary to deletion of shelterin protein TRF1 in specific cell types has modeled organ-specific pathologic changes attributed to human syndromes of telomere dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Telomere Dysfunction Drives Chronic Lung Allograft Dysfunction Pathology

Naikawadi¹,

Green²,

Jones³

et al. 2019

Preprint

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Rationale:Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD) which is a major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Objective:Our objective was to test whether telomere dysfunction contributes to pathologic changes seen in CLAD. Methods and Results:Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells (AECs), and increased expression of senescence markers (beta-galactosidase, p16, p53 and p21) in lung epithelial cells. Telomere repeat binding factor 1 flox/flox (TRF1 F/F ) mice were crossed with tamoxifen inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1 F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on micro-computed tomography, a 4fold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II AEC numbers, expression of senescenceassociated beta-galactosidase in epithelial cells and decreased SCGB1a1 expression in airway epithelial cells. Conclusions:These findings demonstrate that telomere dysfunction isolated to club cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.

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“…21,22 Another use of patient-specific iPSCs is in vitro disease modeling. Although iPSC-derived cardiomyocytes are relatively immature, they manifest some features of cardiomyopathy, such as arrhythmias, channelopathies, hypertrophy, premature telomere shortening, and dilated cardiomyopathy [22][23][24] and are used to investigate mechanisms of pathogenesis and to screen drugs.…”

Section: The He a Rtmentioning

confidence: 99%

“…The derivation of ESCs and iPSCs fueled expectations for cell-replacement therapy, but its greatest effect has been in basic research into the mechanisms of tissue differentiation and the pathophysiology of human disease. Dozens of disorders have been modeled in vitro with the use of patient-derived iPSCs, [22][23][24]81,82 and extensive screening to overcome disease phenotypes has yielded drug candidates. 83,84 Relatively few clinical interventions have been tested to date, and proof of efficacy for tissuereplacement therapies remains an aspiration.…”

Section: Challengesmentioning

confidence: 99%