Increased Tenascin-C expression contributes to cardiac dysfunction and fibrosis in Duchenne muscular dystrophy
Bibliographic record
Abstract
Abstract Introduction and aims Cardiac fibrosis is characterized by the net accumulation of extracellular matrix (ECM) proteins in the cardiac interstitium and contributes to cardiac contractile dysfunction. In Duchenne muscular dystrophy (DMD), cardiomyopathy develops as a result of a dystrophin deficiency causing fibrofatty replacement of the myocardium, however the underlying mechanisms are not fully understood. There is a growing collection of evidence that ECM proteins, including Tenascin C (TN-C), plays a maladaptive role in left ventricular (LV) remodelling and cardiac fibrosis in ischemic heart disease. The aims of our study were 1) to assess TN-C levels, fibrosis and cardiac dysfunction in DMD patients, and 2) to clarify the role of TN-C in cardiovascular dysfunction and fibrosis using male mdx (n=10) and mdx TN-C KO mice (n=8). Results In male patients with DMD (n=18) and age matched controls (n=12) undergoing cardiac MRI, we detected greater myocardial fibrosis than in control hearts. In addition, we observed an elevation of TN-C plasma levels [median concentration (3.55); interquartile range (0.61–7.43) ng/mL] in DMD patients, and its expression negatively correlated to LV ejection fraction (EF) [median LVEF (45); interquartile range (37.5–51.5) %]. Male wt, mdx and mdx TN-C KO age-matched (10 months) mice were used. Transthoracic echocardiography was performed and fibrosis was assessed on cardiac tissue sections. Wire myography was used to assess vascular endothelial function. To explore the signalling pathways contributing to cardiac fibrosis, human cardiac fibroblasts (hCFs) were treated with recombinant human TN-C or TGF-β and gene expression and epigenetic regulation of NF-kB/p65 were assessed. Mdx mice showed significantly increased cardiac fibrosis which was accompanied with markedly elevated TN-C level in cardiac tissue and plasma compared to wt animals (p<0.05, respectively). Moreover, TN-C level in plasma correlated positively with the degree of cardiac dilation in dystrophic mice. In addition, vascular endothelial function was notably impaired in mdx mice. In contrast, we observed preserved vascular function in mdx- TN-C KO mice, this was accompanied by a significant reduction in cardiac fibrosis in compared to age-matched mdx mice (p<0.05, respectively). hCFs treated with TN-C or TGF-β showed increased collagen and α-SMA expressions which could be prevented by application of siRNA against TN-C. In addition, both TN-C and TGF-β caused p65/NF-κB promoter demethylation and subsequently triggered pro-inflammatory and pro-fibrotic signalling, which could be reversed by applying p38 MAPK inhibitor in hCFs. Conclusion TN-C is a critical component of cardiac fibrosis and cardiac dysfunction in DMD. The activation of NF-κB p65 signalling pathway may play a role in TN-C induced fibrosis. Thus, TN-C may be a mediator and potential target for therapy in DMD-associated cardiovascular complications. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Österreichische MuskelforschungFWF - Austrian Science Found P 35878
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".