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Ribonucleoprotein (RNP) granules are biomolecular condensates--liquid-liquid phase-separated droplets that organize and manage messenger RNA metabolism, cell signaling, biopolymer assembly, biochemical reactions and stress granule responses to cellular adversity. Dysregulated RNP granules drive neuromuscular degenerative disease but have not previously been linked to heart failure. By exploring the molecular basis of congenital dilated cardiomyopathy (DCM) in genome-edited pigs homozygous for an RBM20 allele encoding the pathogenic R636S variant of human RNA-binding motif protein-20 (RBM20), we discovered that RNP granules accumulated abnormally in the sarcoplasm, and we confirmed this finding in myocardium and reprogrammed cardiomyocytes from patients with DCM carrying the R636S allele. Dysregulated sarcoplasmic RBM20 RNP granules displayed liquid-like material properties, docked at precisely spaced intervals along cytoskeletal elements, promoted phase partitioning of cardiac biomolecules and fused with stress granules. Our results link dysregulated RNP granules to myocardial cellular pathobiology and heart failure in gene-edited pigs and patients with DCM caused by RBM20 mutation. Dysregulation of ribonucleoprotein complex granules, previously implicated in neuromuscular disease, can drive pathogenesis in a genetic form of dilated cardiomyopathy, as shown in gene-edited pigs and patient-derived cardiomyocytes., Author(s): Jay W. Schneider [sup.1] [sup.2] , Saji Oommen [sup.1] , Muhammad Y. Qureshi [sup.1] , Sean C. Goetsch [sup.2] , David R. Pease [sup.1] , Rhianna S. Sundsbak [sup.1] [...]

Author(s): Jay W. Schneider [sup.1] [sup.2], Saji Oommen [sup.1], Muhammad Y. Qureshi [sup.1], Sean C. Goetsch [sup.2], David R. Pease [sup.1], Rhianna S. Sundsbak [sup.1], Wei Guo [sup.3] [sup.12], Mingming [...]

The regulation of myogenic progenitor cells during muscle regeneration is not clearly understood. We have previously shown that the Foxk1 gene, a member of the forkhead/winged helix family of transcription factors, is expressed in myogenic progenitor cells in adult skeletal muscle. In the present study, we utilize transgenic technology and demonstrate that the 4.6 kb upstream fragment of the Foxk1 gene directs beta-galactosidase expression to the myogenic progenitor cell population. We further establish that Sox15 directs Foxk1 expression to the myogenic progenitor cell population, as it binds to an evolutionarily conserved site and recruits Fhl3 to transcriptionally coactivate Foxk1 gene expression. Knockdown of endogenous Sox15 results in perturbed cell cycle kinetics and decreased Foxk1 expression. Furthermore, Sox15 mutant mice display perturbed skeletal muscle regeneration, due in part to decreased numbers of satellite cells and decreased Foxk1 expression. These studies demonstrate that Sox15, Fhl3 and Foxk1 function to coordinately regulate the myogenic progenitor cell population and skeletal muscle regeneration.