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Cardiomyocytes Among Physiology and Pathophysiology: Molecular Insights and Therapeutic Implications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 3568

Special Issue Editors


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Guest Editor
Institute of Clinical Physiology, CNR, Via Moruzzi 1, 56124 Pisa, Italy
Interests: cardiovascular disease; cardiomyocyte; cardiac troponin; heart failure; atherosclerosis

Special Issue Information

Dear Colleagues,

Among all developing organs, the heart is the first to become functionally active during embryogenesis. Cardiac development is orchestrated by a complex and highly regulated network of molecular and metabolic pathways involving various cell types. These networks integrate signaling molecules, transcriptional regulators, and metabolic cues to ensure the proper formation and function of the heart. Cardiomyocytes, the contractile cells of the myocardium, convert chemical energy into mechanical force through myosin ATPases, which utilize high-energy phosphate compounds to power the cross-bridge cycling of sarcomeres.

Perturbations in the molecular mechanisms that govern cardiac development and sarcomere organization—whether of genetic or epigenetic origin—can lead to a spectrum of congenital heart defects (CHDs), among which ventricular septal defects (VSDs) represent the most prevalent subtype.

Historically, the adult mammalian heart was considered a terminally differentiated organ with negligible regenerative potential. However, accumulating evidence indicates that physiological stimuli, such as endurance exercise, can promote cardiomyocyte renewal. This regenerative response is believed to be mediated, at least in part, by epigenetic reprogramming involving non-coding RNAs. Elucidating the molecular pathways activated by exercise may uncover novel therapeutic targets for enhancing cardiac regeneration, particularly in the context of ischemic injury.

Conversely, cardiac aging is characterized by progressive declines in contractile function, mitochondrial integrity, and telomere length, alongside increases in myocardial mass and fibrosis. The cumulative burden of senescent and dysfunctional cardiomyocytes impairs intracellular signaling, promotes chronic low-grade inflammation, exacerbates metabolic stress, and contributes to adverse structural remodeling, including hypertrophy and cell death.

This Special Issue aims to explore the molecular and cellular regulatory mechanisms underlying cardiac development, regeneration, and aging. A deeper understanding of these processes will be essential for the development of targeted therapies for congenital anomalies, myocardial injury, and age-associated cardiovascular pathologies.

Dr. Rosetta Ragusa
Dr. Chiara Caselli
Guest Editors

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Keywords

  • sarcomere
  • metabolic stress
  • epigenetic mechanisms
  • exercise
  • aging

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Published Papers (3 papers)

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Research

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21 pages, 2951 KB  
Article
Western Diet-Induced Impairment of Left Atrium Cardiomyocyte Contractility in Female Wistar Rats Is Associated with Slowdown in the Cross-Bridge Cycle and Dephosphorylation of cMyBP-C
by Elena Mukhlynina, Xenia Butova, Tatiana Myachina, Raisa Simonova, Yulia Antonets, Anna Leiberova, Anastasia Kochurova, Evgeniya Gusarova, Tatiana Chumarnaya, Galina Kopylova and Daniil Shchepkin
Int. J. Mol. Sci. 2026, 27(3), 1508; https://doi.org/10.3390/ijms27031508 - 3 Feb 2026
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Abstract
Obesity is a major risk factor for heart failure and atrial fibrillation. This study investigated the effects of diet-induced obesity on the molecular and cellular mechanisms of cardiomyocyte contractility in the left and right atria (LA and RA). Female Wistar rats were fed [...] Read more.
Obesity is a major risk factor for heart failure and atrial fibrillation. This study investigated the effects of diet-induced obesity on the molecular and cellular mechanisms of cardiomyocyte contractility in the left and right atria (LA and RA). Female Wistar rats were fed a Western diet (WD) for 18 weeks. Sarcomere dynamics and calcium transients were measured in unloaded cardiomyocytes. Actin–myosin interactions and contractile protein phosphorylation were assessed via an in vitro motility assay and phosphoprotein-specific gel electrophoresis. WD-fed rats developed obesity, hypertension, and metabolic alterations in the absence of echocardiographic or histological evidence of cardiac remodeling or systolic dysfunction. In LA cardiomyocytes, contractile dysfunction was indicated by increased calcium transient amplitude coupled with reduced shortening amplitude and relengthening velocity. This functional impairment correlated with a slowed myosin cross-bridge cycle and dephosphorylation of cMyBP-C. In contrast, RA cardiomyocytes displayed only molecular changes in response to obesity, including altered phosphorylation of most sarcomeric proteins and a decelerated cross-bridge cycle, but showed no evident contractile dysfunction. Thus, an 18-week WD reflects the early stages of contractile impairment, where functional deficits are specific to the LA, while RA alterations are confined to the molecular level. Full article
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18 pages, 1262 KB  
Article
Atorvastatin Protects Against Deleterious Carfilzomib-Induced Transcriptional Changes in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
by Marwa Tantawy, Danxin Wang, Mohammed Gbadamosi, Fahong Yu, Yanping Zhang, Mohammed E. Alomar, Kenneth H. Shain, Rachid C. Baz, Katelyn A. Bruno and Yan Gong
Int. J. Mol. Sci. 2026, 27(3), 1358; https://doi.org/10.3390/ijms27031358 - 29 Jan 2026
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Abstract
The mechanisms underlying carfilzomib (CFZ)-induced cardiotoxicity remain incompletely elucidated. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to characterize the transcriptional impact of CFZ and to evaluate whether atorvastatin could prevent these deleterious transcriptional changes. hiPSC-CMs were treated with [...] Read more.
The mechanisms underlying carfilzomib (CFZ)-induced cardiotoxicity remain incompletely elucidated. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to characterize the transcriptional impact of CFZ and to evaluate whether atorvastatin could prevent these deleterious transcriptional changes. hiPSC-CMs were treated with 1 µM CFZ, CFZ + atorvastatin, atorvastatin, or vehicle control, followed by RNA sequencing, differential expression analyses, and pathway analyses. Transcriptomic profiling revealed a marked upregulation of genes in multiple proteasome subunits, including ATPase components (PSMC1, PSMC4, PSMC5, PSMC6) and non-ATPase regulatory subunits (PSMD1, PSMD2, PSMD12), suggesting a strong compensatory activation of proteostasis and protein quality-control pathways in response to CFZ exposure. In addition, several of the most significantly altered genes were those implicated in cardiomyopathy and heart failure, such as BAG3 and FLNC, and many heat-shock proteins, indicating the activation of cardiac stress–response pathways relevant to CFZ-associated cardiotoxicity. Atorvastatin co-treatment partially reversed a subset of CFZ-induced transcriptional changes, particularly within cholesterol biosynthesis and lipid-regulatory pathways (e.g., ACAT2 and ACTA1) but did not restore the CFZ-mediated downregulation of sarcomeric genes. Together, these findings define a multifactorial signature of deleterious CFZ-induced transcriptional changes and suggest that atorvastatin may provide partial metabolic, but not structural, cardio protection. Full article
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Review

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29 pages, 2502 KB  
Review
Non-Coding RNA Profile in the Progression of Carotid Atherosclerosis: A Systematic Review
by Gemma Sardelli, Pasquale Bufano, Rosetta Ragusa, Marco Laurino, Gabriele Masini, Luna Gargani, Danilo Neglia, Raffaele De Caterina and Chiara Caselli
Int. J. Mol. Sci. 2026, 27(2), 1002; https://doi.org/10.3390/ijms27021002 - 19 Jan 2026
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Abstract
Carotid atherosclerosis remains one of the primary etiological factors underlying ischemic stroke, contributing to adult neurological disability and mortality. In recent years, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, actively modulating molecular pathways involved in atherogenesis. This systematic review, [...] Read more.
Carotid atherosclerosis remains one of the primary etiological factors underlying ischemic stroke, contributing to adult neurological disability and mortality. In recent years, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, actively modulating molecular pathways involved in atherogenesis. This systematic review, the first to be exclusively focused on carotid atherosclerosis, aimed at synthesizing current findings on the differential expression of ncRNAs throughout the natural history of the disease, thus providing the first comprehensive attempt to delineate a stage-specific ncRNA expression profile in carotid disease. A comprehensive literature search was conducted in PubMed and Scopus databases in January 2025, following PRISMA guidelines. Original studies involving human subjects with carotid atherosclerosis, evaluating the expression of intracellular or circulating ncRNAs, were included and then categorized according to their association with cardiovascular risk factors, carotid intima-media thickness (cIMT), presence of atherosclerotic plaques, plaque vulnerability, clinical symptoms, and ischemic stroke. Out of 148 articles initially identified, 49 met the inclusion criteria and were analyzed in depth. Among the different classes of ncRNAs, microRNAs (miRNAs) were the most frequently reported as dysregulated, followed by circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Notably, the majority of identified ncRNAs were implicated in key pathogenic mechanisms such as inflammatory signaling, vascular smooth muscle cell (VSMC) phenotypic modulation, and ABCA1-mediated cholesterol efflux. Collectively, the evidence underscores the association and possible involvement of ncRNAs in the initiation and progression of carotid atherosclerosis and its cerebrovascular complications. Their relative stability in biological fluids and cell-specific expression profiles highlight their strong potential as minimally invasive biomarkers and—possibly—novel therapeutic targets. Full article
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