{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Melusin, the muscle‐specific chaperone protein encoded by the "}, {"type": "b", "children": [{"type": "t", "text": "ITGB1BP2"}]}, {"type": "t", "text": " gene, interacts with the cytoplasmic domain of β1 integrin and functions as a critical mechanosensor in striated muscle. Its engagement with other components of the integrin complex helps transduce mechanical stress into biochemical signals that promote adaptive cardiac hypertrophy. For example, in murine models, loss of melusin expression impairs hypertrophic responses to pressure overload and leads to maladaptive left ventricular remodeling, thereby precipitating dilated cardiomyopathy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, melusin is an essential part of a supramolecular complex containing kinases and scaffold proteins such as focal adhesion kinase, IQGAP1, and Hsp90, which together regulate the activation of ERK1/2 and Akt pathways—a signaling axis that is vital for cardiomyocyte survival and compensatory growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Sequence analyses have revealed that melusin arose via a gene duplication event that produced a ubiquitously expressed homolog (chp‐1) and a specialized, muscle‐restricted isoform, underscoring its evolutionarily tailored role in mechanotransduction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Human genetic studies further indicate that mutations and single nucleotide polymorphisms in ITGB1BP2 are extremely rare and unlikely to account for a major proportion of cardiomyopathies, although subtle regulatory variations may modify disease progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Furthermore, dynamic regulation of melusin expression—modulated by both mechanical and neurohormonal stimuli—has been correlated with altered activation of kinases such as Akt, GSK3β, and CDC42 during post‐myocardial infarction remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In transgenic models, melusin overexpression confers cardioprotective benefits by attenuating myocardial infarction–induced damage and reducing the incidence of cardiac rupture."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these findings establish melusin as a pivotal integrin-linked mechanotransducer that orchestrates intracellular signaling in response to biomechanical stress, thereby preserving myocardial integrity and function.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mara Brancaccio, Luigi Fratta, Antonella Notte, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Melusin, a muscle-specific integrin beta1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm805"}], "href": "https://doi.org/10.1038/nm805"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12496958"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12496958"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mauro Sbroggiò, Alessandro Bertero, Silvia Velasco, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.091140"}], "href": "https://doi.org/10.1242/jcs.091140"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22010199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22010199"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mauro Sbroggiò, Roberta Ferretti, Elena Percivalle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The mammalian CHORD-containing protein melusin is a stress response protein interacting with Hsp90 and Sgt1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2008.04.058"}], "href": "https://doi.org/10.1016/j.febslet.2008.04.058"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18474241"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18474241"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mara Brancaccio, Nadia Menini, Daniela Bongioanni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chp-1 and melusin, two CHORD containing proteins in vertebrates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0014-5793(03)00892-5"}], "href": "https://doi.org/10.1016/s0014-5793(03"}, {"type": "t", "text": "00892-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12965203"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12965203"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Volker Ruppert, Thomas Meyer, Anette Richter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a missense mutation in the melusin-encoding ITGB1BP2 gene in a patient with dilated cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2012.10.055"}], "href": "https://doi.org/10.1016/j.gene.2012.10.055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23124043"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23124043"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Valeria Palumbo, Ludovica Segat, Lara Padovan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Melusin gene (ITGB1BP2) nucleotide variations study in hypertensive and cardiopathic patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2350-10-140"}], "href": "https://doi.org/10.1186/1471-2350-10-140"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20017903"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20017903"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Rong Gu, Di Zheng, Jian Bai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered melusin pathways involved in cardiac remodeling following acute myocardial infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Pathol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.carpath.2011.03.002"}], "href": "https://doi.org/10.1016/j.carpath.2011.03.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21546274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21546274"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "J Aro, H Tokola, V-P Ronkainen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of cardiac melusin gene expression by hypertrophic stimuli in the rat."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Physiol (Oxf) (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/apha.12044"}], "href": "https://doi.org/10.1111/apha.12044"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23198998"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23198998"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Bernhard Unsöld, Axel Kaul, Mauro Sbroggiò, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvt235"}], "href": "https://doi.org/10.1093/cvr/cvt235"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24130190"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24130190"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Claudia Penna, Mara Brancaccio, Francesca Tullio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Basic Res Cardiol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00395-014-0418-9"}], "href": "https://doi.org/10.1007/s00395-014-0418-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24859929"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24859929"}]}]}]}