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Molecular Insights into the Role of Desmin Intermediate Filament Network in Chromatin Landscape, Early Cardiogenic Commitment and Cardiomyocyte Differentiation and Maturation (HiC)

ABSTRACT: The cardiac cytoskeleton is essential for the proper intracellular and intercellular integration of structure and function, failure of which leads to heart disease. However, its role during development and cardiac differentiation is often overlooked. Here, we sought to understand the role of the desmin intermediate filament cytoskeletal network in cardiac cell differentiation and homeostasis during embryonic development, post birth, adulthood and upon different stimuli. We show that desmin is highly expressed in cardiac progenitor cell populations during embryogenesis. In addition, using direct cellular reprogramming of fibroblasts to induced cardiomyocytes, we demonstrated that ectopic desmin expression directly influences cardiomyogenesis through a timely transcriptional regulation of the Notch1 signaling pathway. On the contrary, the absence of desmin in induced cardiomyocytes leads to substantial perturbations in cardiac maturation by diminishing the expression and proper localization of cardiac specific proteins, impairing calcium homeostasis and delaying myofibril formation. RNA and ChIP sequencing, along with chromosome conformation capture (HiC) in desmin-depleted cardiomyocytes revealed that the observed gene expression changes reflect the identified corresponding changes in chromatin architecture that cause loss of genome organization and thus contributing to pathophysiological phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE274607 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:Background: Mutations of the desmin gene cause familial and sporadic cardiomyopathies and myopathies. Previous studies showed that both the lack of desmin and expression of mutated desmin negatively impact on number, structure and function mitochondria implying a metabolic dysfunction as disease promoting factor. Here, we exploited desmin knock-out mice to analyse the general metabolic performance of cardiac tissue. Methods: We analysed left ventricular cardiac muscle tissue derived from six-month-old homozygous desmin knock-out mice as well as wild-type siblings. Employing a multi-method approach comprising morphological, clinical chemistry, biochemical, genetic, and proteomic techniques, we specifically addressed energy, fatty acid, glucose, and amino acid metabolism. Results: We demonstrated that the lack of desmin in left ventricular cardiac tissue led to a significant decrease in the number of mitochondria in conjunction with ultrastructural defects of mitochondria. Analysis of mitochondria-related metabolic pathways revealed significantly impaired processes of fatty acid transport, activation, and catabolism associated with increased blood levels of short, medium, and long chain acyl-carnitines. In addition to increased amounts of glucose transporter 1 and hexokinase 1, we detected a significantly increased hexokinase enzyme activity. While the amount of mitochondrial creatine kinase was markedly reduced, fetal creatine kinase was increased. The picture of a highly dysbalanced metabolic state was complemented by our quantitative proteomic analysis that revealed significantly reduced levels of multiple proteins centrally involved in electron transport mainly of complexes I and II, oxidative phosphorylation, citrate cycle, beta oxidation including auxiliary pathways, amino acid catabolism, and redox reactions and oxidative stress. Conclusions: Our data denoted a picture of widespread metabolic dysfunction far reaching beyond the level of mitochondria in left ventricular cardiac tissue of desmin knock-out mice. The increase of glucose utilisation along with increased level of fetal creatine kinase likely is a compensatory measure counteracting the severely hampered fatty acid metabolism and oxidative phosphorylation. The degree of metabolic disbalance, already observed in desmin knock-out mice kept under standard ‘sedentary’ housing conditions, renders it likely that acute strenuous physical exercise with its steeply increased energy demand will push the cardiac tissue into severe metabolic crisis.

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Molecular Insights into the Role of Desmin Intermediate Filament Network in Chromatin Landscape, Early Cardiogenic Commitment and Cardiomyocyte Differentiation and Maturation (HiC)

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