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Titin truncation and haploinsufficiency in human dilated cardiomyopathy

Commented by the ESC WG on Myocardial Function

Pathophysiology and Mechanisms

The giant molecule, titin, which constitutes an integral part of cardiac and skeletal muscle sarcomere, serves essential roles in sustaining normal cardiac structure and function. Therefore, titin abnormalities caused by heterozygous truncating variants of the titin gene (TTNtv) have been implicated in the pathogenesis of various cardiac pathologies, including amongst others, dilated cardiomyopathy (DCM) and cardiac arrhythmia. However, thus far it remained incompletely understood how prevalent and etiologically relevant are these mutations, thereby hindering the exploitation of titin as an actionable target for therapeutic cardiac interventions.

In their recent paper, Fomin and colleagues comprehensively examined titin and related TTNtv expression levels in a cohort of over 100 patients with end-stage DCM, thereby showing that almost every fifth patient exhibits such mutations. This finding holds major significance, as such high prevalence was not anticipated. Hearts with TTNtv also exhibited a global titin haploinsufficiency in association with titin truncation, compared to both non-TTNtv DCM hearts as well as healthy donor hearts. Interestingly, the expression of truncated titin inversely correlated with the patient’s age at transplantation, suggesting that increased titin truncation might accelerate DCM and, thus, the need for a transplant. In fact, left ventricular ejection fraction tended to correlate, albeit mildly, with the increase in titin truncation as well as the decrease in overall titin expression. The authors went forward to show that truncated titin is not incorporated into the sarcomere, at least not in detectable amounts. Instead, truncated titin was sequestrated into intracellular protein aggregates, thereby deteriorating cardiomyocyte protein quality control mechanisms.

In support of this notion, titin ubiquitination was generally increased in DCM, but more so in TTNtv DCM hearts, compared to non-failing controls. However, specific ubiquitination of truncated titin was low, despite their abundance, which might denote insufficient degradation. In fact, the E3-ubiquitin ligase, MURF1 (muscle RING-finger protein-1), which mediates the proteasomal degradation of various sarcomere proteins, including titin, was significantly reduced in TTNtv, but not in non-TTNtv, hearts with DCM, as compared to non-failing donor hearts. By contrast, autophagy, another degradative pathway essential for cellular quality control, appeared to be equally activated in both DCM groups, as indicated by reduced expression levels of the autophagic substrate p62 and increased autophagy-associated lipidation of the microtubule-associated protein 1A/1B-light chain 3B (LC3B). Consistently, examining various pharmacological modulators of autophagy and the ubiquitin proteosome system (UPS) revealed that UPS is more involved in regulating truncated titin levels than autophagy. In fact, the mechanical performance of an engineered heart muscle (EHM) generated from TTNtv-hiPSC-CMs, could be even rescued using UPS inhibitors. Of note, this effect occurred despite an expected accumulation of truncated titin, and might be driven by the parallel increase in the total cellular content of normal titin. Regardless, CRISPR-Cas9–mediated gene correction, which effectively reduced titin truncation, had an even superior beneficial effect in correcting the contractile deficit observed in TTNtv-bearing EHM.

Taken together, the authors are to be commended on their efforts to elucidate the prevalence and mechanisms regulating titin truncation and its role in DCM. Future research should build on these ground-breaking findings to identify potential actionable targets to correct titin haploinsufficiency and truncation in patients with DCM without having to completely block protein quality control mechanisms, which might inadvertently impair other cardiac functions. Until then, gene editing using emerging CRISPR-Cas9 technology might be perhaps worth considering.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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