Integrative transcriptomic profiling links telomere dysfunction to cGAS-STING activation in heart failure signatures in mice and humans.

Telomerase-deficient mice (mTRG5) developed progressive cardiac dysfunction accompanied by confirmed telomere shortening.

• Mice were generated until generation 5 (mTRG5) to achieve cumulative telomere shortening.
• Cardiovascular phenotyping confirmed increasing cardiac dysfunction across generations.
• Cardiomyocyte mitochondrial function was assessed and showed repression consistent with the telomere-p53-mitochondria axis.
• The model confirmed engineered telomerase deficiency as a driver of myocardial dysfunction.

Transcriptional analysis of mTRG5 mice revealed activation beyond the telomere-p53-mitochondria axis, including neurohumoral activation, senescence, inflammation, and notably type I interferon signaling.

• Regulator analysis confirmed the telomere-p53-mitochondria axis as a primary pathway.
• Additional transcriptional programs identified included neurohumoral activation and cellular senescence.
• Type I interferon signaling was identified as a notable additional component of the mTRG5 transcriptional profile.
• These findings extended beyond previously established pathways in telomerase-deficient cardiac dysfunction.

In mTRG5 mice, regulators of telomere dysfunction and p53 activation ranked highest by significance and centrality, supporting telomere shortening as the primary upstream driver of the transcriptional hierarchy.

• The study compared mTRG5 profiles with hypertensive heart failure induced by neurohumoral dysregulation (angiotensin II infusion, nephrectomy, salt overload; ANS model).
• A transcriptional hierarchy was established by comparing these two models.
• In ANS mice, neurohumoral regulators ranked higher, indicating these govern secondary pathways rather than primary drivers.
• Reciprocal ranking between models supported the conclusion that each model's primary pathology drives its highest-ranked regulators.

cGAS-STING pathway activation was confirmed in mTRG5 mice, providing first evidence for cGAS-STING activation in the context of telomere shortening and heart failure.

• Mice lacking three-prime exonuclease 1 (TREX1), an established activator of the cGAS-STING pathway, were used to establish a reference transcriptional profile for cGAS-STING activation.
• Matching of TREX1-deficient profiles with mTRG5 profiles confirmed pronounced cGAS-STING activation in mTRG5 mice.
• ANS mice showed slightly less cGAS-STING activation compared to mTRG5 mice.
• The authors describe this as 'first evidence for cGAS-STING activation in telomere shortening and heart failure.'

The mTRG5 transcriptional signature showed robust cross-species and cross-etiology overlap with murine and human dilated and ischemic cardiomyopathy datasets.

• Integration was performed with curated transcriptomic datasets from both murine and human dilated cardiomyopathy and ischemic cardiomyopathy.
• Overlap increased with heart failure severity.
• Overlap decreased with functional recovery.
• The findings demonstrated relevance of the telomere dysfunction signature across species and multiple heart failure etiologies.

Cardiomyocyte telomere shortening is evident during heart failure pathogenesis, and mice with engineered telomerase deficiency develop myocardial dysfunction accompanied by p53 activation and mitochondrial repression.

• This relationship between telomere shortening and cardiac dysfunction is established in the background of the study.
• p53 activation and mitochondrial repression are described as accompanying features of telomerase deficiency-driven myocardial dysfunction.
• The study aimed to determine whether cardiac dysfunction arises from myocardial-intrinsic effects or systemic consequences of telomere shortening.