Damage control in broken heart: DNA damage response as a common path in arrhythmogenic cardiomyopathy

This editorial refers to ‘Haplo-insufficiency of Tmem43 in cardiac myocytes activates the DNA damage response pathway leading to a Late-Onset Senescence-Associated pro-fibrotic cardiomyopathy’ by L. Rouhi et al., pp. 2377–2394. Arrhythmogenic cardiomyopathy (ACM) is a rare condition characterized by electrocardiogram abnormalities and fibrofatty remodelling in ventricular myocardium with potentially lethal consequences particular among the affected young athletes.1 ACM is largely an inherited disease, however, the genetic lesions for almost half of the patient population remain to be identified and the penetrance is also highly variable.2 Therefore, ACM can be viewed as a collection of diseases with common symptoms but contributed by complex genetic and environmental factors.3 Among the known genetic variants associated with ACM, desmosomal and cell–cell junctional components at intercalated disc and structural components of nuclear membrane represent the majority of the affected genes.4 Decoding the underlying pathophysiological mechanisms in ACM-specific remodelling and electrical disturbance caused by these genetic lesions has been a longstanding quest in the field. Thanks to the recent successes in the development of animal models through targeted genome editing, it is now feasible to interrogate the pathogenic process of the disease at molecular and cellular levels.5 In this issue, a report by Rouhi et al.6 provides some important new insights to the molecular underpinnings of the disease based on their characterization in a mouse model carrying cardiomyocyte-specific haplo-deficiency of Tmem43, one of the causal genes of ACM. Tmem43 is a transmembrane protein located at nuclear inner surface with poorly annotated molecular function. A Tmem43p.Ser358Leu allele was first established as a causal genetic variant for ACM Type V in a cohort from Newfoundland, Canada. Recently, mouse models expressing the Tmem43p.Ser358Leu mutant protein in heart was developed and shown to recapitulate some of the ACM phenotypes, including the characteristic fibrofatty replacement, electrical abnormalities, and premature death.7,8 While this evidence supports a dominant effect of Tmem43p.Ser358Leu allele in the pathogenesis of ACM, other null mutations of Tmem43 have also been found in ACM patients, raising the prospect that Tmem43 loss of function mutation is also an alternative pathogenic mechanism. In this study by Rouhi et al.,6 cardiomyocyte-specific deletion of one allele of the mouse tmem43 gene was accomplished using an αMHC driving cre-loxp-mediated gene deletion. TMEM43 expression was detected in different cell types in heart; therefore, cardiac-specific deletion of tmem43 gene offered an opportunity to evaluate cardiomyocyte-autonomous effects of its deficiency in heart. The Tmem43 deficient mice were indistinguishable from the normal controls at morphological and functional levels up to 4 months of age, however, significant cardiac pathologies developed over time. At 9 months of age, myocyte hypertrophy, interstitial fibrosis, ventricular chamber dilation, signs of lipogenesis, and apoptosis were observed in the Tmem43 deficient hearts. Premature death was observed from 9 to 10 months of age, leading to near complete loss of animals by about 15 months of age. In order to capture the molecular changes prior to and during these pathological manifestations, the transcriptome profiles were determined by RNA-seq in 4 months and 9 months old hearts. Among the differentially expressed genes detected in the 4-month-old Tmem43 deficient heart, enrichment in TP53 targets was the only feature identified, implicating TP53 activation as a potential early molecular driver leading to the onset of cardiomyopathy. This speculation was confirmed in the 9 months old hearts based on demonstrations of the activation TP53 and its known target genes. In addition, molecular signatures associated with DNA damage response (DDR) and senescence-associated secretary phenotype were detected in the Tmem43 deficient hearts along with marked induction of TGFβ/Smad pathway. These results prompted authors to conclude that DDR and ensuring TP53 activity were triggered in the Tmem43 deficient myocytes, leading to the activation of pro-fibrotic remodelling and dysfunction.6 Interestingly, similar molecular changes were also observe in dilated cardiomyopathy associated with Lamin A/C (LMNA) mutations, a Tmem43 interacting partner also associated with ACM.9 Therefore, DDR and TP53 activation appear to be a common molecular feature caused by compromised nuclear-membrane integrity due to Tmem43 or LMNA mutations during the pathogenesis of ACM-related cardiomyopathy (Figure 1). Illustration of potential mechanisms involving DDR in the pathogenesis of ACM. Illustration of potential mechanisms involving DDR in the pathogenesis of ACM. Although the data presented by Rouhi et al. was both comprehensive and compelling, these results are still observational and correlative in nature. The direct causal role of DDR induction and TP53 activation in the pathogenesis of ACM-related cardiomyopathy needs to be validated directly by either genetic or pharmacological interventions. In addition, despite of a lethal outcome, this mouse model lacks clear evidence of electrophysiological abnormalities and rampant induction of intracardiac fat, the two most prominent pathological features of ACM. It is not clear whether the difference is due to the limited impact of Tmem43 deficiency in cardiomyocytes or species-specific outcome between rodent and human. Therefore, direct translation of this finding to ACM mechanism in human should be viewed with caution. Nevertheless, Tmem43 and Lamin A/C are interacting partners co-localized at nuclear membrane. A shared molecular signature in DDR resulted from their individual defect raises interesting possibility for their joint role in maintaining genome integrity in cardiomyocytes. It is possible that mechanical stretch during myocyte contraction can impose accumulative damage to myocyte genome over time, especially when nuclear membrane is compromised due to genetic lesions. This insight not only offers a potential unified mechanism for cardiomyopathy associated with nuclear-membrane proteins, but also points to a tantalizing strategy for possible therapies. Like GSK3β and NF-kB are identified as possible targets to improve pathological outcome in the Tmem43p.Ser358Leu hearts,7,8 cardiomyopathy related to Tmem43 deficiency may be ameliorated by modulating DDR and the ensuing signalling. Finally, this and prior studies clearly demonstrate that distinct phenotypes and cellular pathways can be generated from two different kinds of Tmem43 mutations, another reminder of the enormous complexity in ACM pathogenesis. Therefore, much work in our current quest to fully dissect the genetic basis and the underlying mechanisms of ACM is still ahead of us. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.