{
  "abstract": "Rhythmic contraction and relaxation of the myocardium impose continuous mechanical forces on cardiomyocyte nuclei via the cytoskeleton. Nuclear invaginations (NI), inward folds of the nuclear envelope, are observed in cardiomyocytes and are believed to be important for the cell contractile function.1 However, the mechanism behind the formation of NI and their functional roles remains unclear.Adult rat, control and 8 weeks, 16 weeks Heart Failure (HF) as well as mice SYNE+/+ and -/- cardiomyocytes were used in the study. Cells were subjected to pharmacological and mechanical stimulation. Super-resolution microscopy was used to visualize the nucleus and RNA labelling.Calcium handling was analysed via live confocal imaging with Fluo-4. Mechano-Scanning Ion Conductance Microscopy was obtained to measure cell Young’s modulus.Our findings show that NI are more frequent in left than right ventricular cardiomyocytes. Using pharmacological and genetic approaches, we identified actin and microtubule forces as key regulators of NI formation, highlighting the cytoskeleton’s role in their development. Additionally, the nucleoli were found to contribute to NI formation, suggesting an intranuclear pulling force mechanism. Functionally, NI loss decreased the perinuclear RNA and elevated nuclear Ca2+ levels. Lower NI density also increased DNA breaks and shifted H3K9me3 heterochromatin to H3K27me3. In HF cardiomyocytes, a progressive loss of NI was observed alongside nuclear morphological changes, with early nucleolar alterations preceding microtubular reorganization. Tissue analysis from patients with Dilated Cardiomyopathy revealed similar trends. Furthermore, biomechanical stress (high stiffness and pressure), significantly reduced NI formation.These novel findings suggest that NI are lost early in HF and are critical for maintaining nuclear function, structural integrity, and gene expression, making them essential in both, normal and pathological conditions.Reference Ljuobojevic S, Radulovic S, Leitinger G, et al. Early remodelling of perinuclear Ca2+ stores and nucleoplasmic Ca2+ signalling during the development of hypertrophy and heart failure. Circulation 2014;130:244–255.",
  "authors": [
    {
      "affiliations": [
        "Imperial College London",
        "Queen Mary University London"
      ],
      "name": "Pamela Swiatlowska"
    },
    {
      "affiliations": [
        "Medical University of Graz"
      ],
      "name": "Ingrid Matzer"
    },
    {
      "affiliations": [
        "King’s College London"
      ],
      "name": "Graham Samuel Wilson Darren"
    },
    {
      "affiliations": [
        "King’s College London"
      ],
      "name": "Qiuping Zhang"
    },
    {
      "affiliations": [
        "Queen Mary University London"
      ],
      "name": "Thomas Iskratsch"
    },
    {
      "affiliations": [
        "Medical University of Graz"
      ],
      "name": "Senka Ljubojevic-Holzer"
    },
    {
      "affiliations": [
        "Imperial College London"
      ],
      "name": "Julia Gorelik"
    }
  ],
  "title": "P2  Dynamic remodelling of nuclear invaginations in cardiomyocytes - implications for heart failure",
  "uid": "0fb09745-5300-546d-8b4d-4c71e348bf47"
}