Ablation of palladin in adult heart causes dilated cardiomyopathy associated with intercalated disc abnormalities

Mastrototaro, Giuseppina; Carullo, Pierluigi; Zhang, Jianlin; Scellini, Beatrice; Piroddi, Nicoletta; Nemska, Simona; Filomena, Maria Carmela; Serio, Simone; Otey, Carol; Tesi, Chiara; Emrich, Fabian; Linke, Wolfgang A.; Poggesi, Corrado; Boncompagni, Simona; Bang, Marie Louise

doi:10.7554/elife.78629

Cited by 6 publications

(2 citation statements)

References 90 publications

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“…At several loci, the nearest gene to the most strongly associated variant had a known role in contractility or sarcomere function, including TTN (titin), PALLD (pallidin) 39 , PLEC (plectin) 40 , DSP (desmoplakin) 41,42 and MYO18B (myosin 18b) 43 . Another subset of genes may play active roles in cardiac development (MECOM [44][45][46][47] , ANKRD1 48 , ADPRHL1 [49][50][51] , WNT9b 52 ).…”

Section: Gwas Of Cardiac Age Accelerationmentioning

confidence: 99%

Genetics of Cardiac Aging Implicate Organ-Specific Variation

Brundage,

Barrios,

Tison

et al. 2024

Preprint

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Heart structure and function change with age, and the notion that the heart may age faster for some individuals than for others has driven interest in estimating cardiac age acceleration. However, current approaches have limited feature richness (heart measurements; radiomics) or capture extraneous data and therefore lack cardiac specificity (deep learning [DL] on unmasked chest MRI). These technical limitations have been a barrier to efforts to understand genetic contributions to age acceleration. We hypothesized that a video-based DL model provided with heart-masked MRI data would capture a rich yet cardiac-specific representation of cardiac aging.In 61,691 UK Biobank participants, we excluded noncardiac pixels from cardiac MRI and trained a video-based DL model to predict age from one cardiac cycle in the 4-chamber view. We then computed cardiac age acceleration as the bias-corrected prediction of heart age minus the calendar age. Predicted heart age explained 71.1% of variance in calendar age, with a mean absolute error of 3.3 years. Cardiac age acceleration was linked to unfavorable cardiac geometry and systolic and diastolic dysfunction. We also observed links between cardiac age acceleration and diet, decreased physical activity, increased alcohol and tobacco use, and altered levels of 239 serum proteins, as well as adverse brain MRI characteristics.We found cardiac age acceleration to be heritable (h2g 26.6%); a genome-wide association study identified 8 loci related to linked to cardiomyopathy (nearTTN, TNS1, LSM3, PALLD, DSP, PLEC, ANKRD1andMYO18B) and an additional 16 loci (nearMECOM, NPR3, KLHL3, HDGFL1, CDKN1A, ELN, SLC25A37, PI15, AP3M1, HMGA2, ADPRHL1, PGAP3, WNT9B, UHRF1 and DOK5). Of the discovered loci, 21 were not previously associated with cardiac age acceleration. Mendelian randomization revealed that lower genetically mediated levels of 6 circulating proteins (MSRA most strongly), as well as greater levels of 5 proteins (LXN most strongly) were associated with cardiac age acceleration, as were greater blood pressure and Lp(a). A polygenic score for cardiac age acceleration predicted earlier onset of arrhythmia, heart failure, myocardial infarction, and mortality.These findings provide a thematic understanding of cardiac age acceleration and suggest that heart- and vascular-specific factors are key to cardiac age acceleration, predominating over a more global aging program.

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Section: Gwas Of Cardiac Age Accelerationmentioning

confidence: 99%

Genetics of Cardiac Aging Implicate Organ-Specific Variation

Brundage,

Barrios,

Tison

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…The Ig-domains of Palladin is most homologous to the sarcomeric Z-disk protein myotilin [ 25 ]. Ablation of palladin in the adult heart results in dilated cardiomyopathy with intercalated disc abnormalities [ 32 ]. A decrease of palladin mRNA is found in atrophying skeletal muscle due to food deprivation [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Actin-organizing protein palladin modulates C2C12 cell fate determination

Nguyen,

Hsu,

Ali

et al. 2024

Biochemistry and Biophysics Reports

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Exploring the potential role of palladin in modulating human CAF/ECM functional units

Dolskii,

Alcantara dos Santos,

Andrake

et al. 2024

Cytoskeleton

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Fibroblasts, crucial for maintaining tissue homeostasis, significantly shape the tumor microenvironment (TME). In pancreatic cancer, a highly aggressive malignancy, cancer‐associated fibroblast (CAF)/extracellular matrix (ECM) units dominate the TME, influencing tumor initiation, progression, and treatment responses. Palladin, an actin‐associated protein, is vital for fibroblast structural integrity and activation, playing a key role in CAF/ECM functionality. Palladin interacts with cytoskeletal proteins such as alpha‐actinin (α‐Act) and can therefore regulate other proteins like syndecans, modulating cytoskeletal features, cell adhesion, integrin recycling, and signaling. In this review, we propose that targeting the palladin/α‐Act/syndecan interaction network could modulate CAF/ECM units, potentially shifting the TME from a tumor‐promoting to a tumor‐suppressive state. In silico data and reported studies to suggest that stabilizing palladin‐α‐Act interactions, via excess palladin, influences syndecan functions; potentially modulating integrin endocytosis via syndecan engagement with protein kinase C alpha as opposed to syndecan binding to α‐Act. This mechanism can then affect the distribution of active α5β1‐integrin between the plasma membrane and known intracellular vesicular compartments, thereby influencing the tumor‐suppressive versus tumor‐promoting functions of CAF/ECM units. Understanding these interactions offers likely future therapeutic avenues for stroma normalization in pancreatic and other cancers, aiming to inhibit tumor progression and improve future treatment outcomes.

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Ablation of palladin in adult heart causes dilated cardiomyopathy associated with intercalated disc abnormalities

Cited by 6 publications

References 90 publications

Genetics of Cardiac Aging Implicate Organ-Specific Variation

Genetics of Cardiac Aging Implicate Organ-Specific Variation

Actin-organizing protein palladin modulates C2C12 cell fate determination

Exploring the potential role of palladin in modulating human CAF/ECM functional units

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