{"title":"Msi2增强1型肌营养不良小鼠模型中的肌肉功能障碍。","authors":"","doi":"10.1016/j.bj.2023.100667","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the 3′ untranslated region of the <em>DM1 protein kinase</em> gene. Characteristic degenerative muscle symptoms include myotonia, atrophy, and weakness. We previously proposed an Musashi homolog 2 (MSI2)>miR-7>autophagy axis whereby MSI2 overexpression repressed miR-7 biogenesis that subsequently de-repressed muscle catabolism through excessive autophagy. Because the DM1 HSA<sup>LR</sup> mouse model expressing expanded CUG repeats shows weak muscle-wasting phenotypes, we hypothesized that MSI2 overexpression was sufficient to promote muscle dysfunction <em>in vivo.</em></p></div><div><h3>Methods</h3><p>By means of recombinant AAV murine MSI2 was overexpressed in neonates HSA<sup>LR</sup> mice skeletal muscle to induce DM1-like phenotypes.</p></div><div><h3>Results</h3><p>Sustained overexpression of the murine MSI2 protein in HSA<sup>LR</sup> neonates induced autophagic flux and expression of critical autophagy proteins, increased central nuclei and reduced myofibers area, and weakened muscle strength. Importantly, these changes were independent of MBNL1, MBNL2, and Celf1 protein levels, which remained unchanged upon Msi2 overexpression.</p></div><div><h3>Conclusions</h3><p>Globally, molecular, histological, and functional data from these experiments in the HSA<sup>LR</sup> mouse model confirms the pathological role of MSI2 expression levels as an atrophy-associated component that impacts the characteristic muscle dysfunction symptoms in DM1 patients.</p></div>","PeriodicalId":8934,"journal":{"name":"Biomedical Journal","volume":"47 4","pages":"Article 100667"},"PeriodicalIF":4.1000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S231941702300104X/pdfft?md5=1be53c3ab977b1e60a3e8df7bda4edd9&pid=1-s2.0-S231941702300104X-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Msi2 enhances muscle dysfunction in a myotonic dystrophy type 1 mouse model\",\"authors\":\"\",\"doi\":\"10.1016/j.bj.2023.100667\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the 3′ untranslated region of the <em>DM1 protein kinase</em> gene. Characteristic degenerative muscle symptoms include myotonia, atrophy, and weakness. We previously proposed an Musashi homolog 2 (MSI2)>miR-7>autophagy axis whereby MSI2 overexpression repressed miR-7 biogenesis that subsequently de-repressed muscle catabolism through excessive autophagy. Because the DM1 HSA<sup>LR</sup> mouse model expressing expanded CUG repeats shows weak muscle-wasting phenotypes, we hypothesized that MSI2 overexpression was sufficient to promote muscle dysfunction <em>in vivo.</em></p></div><div><h3>Methods</h3><p>By means of recombinant AAV murine MSI2 was overexpressed in neonates HSA<sup>LR</sup> mice skeletal muscle to induce DM1-like phenotypes.</p></div><div><h3>Results</h3><p>Sustained overexpression of the murine MSI2 protein in HSA<sup>LR</sup> neonates induced autophagic flux and expression of critical autophagy proteins, increased central nuclei and reduced myofibers area, and weakened muscle strength. Importantly, these changes were independent of MBNL1, MBNL2, and Celf1 protein levels, which remained unchanged upon Msi2 overexpression.</p></div><div><h3>Conclusions</h3><p>Globally, molecular, histological, and functional data from these experiments in the HSA<sup>LR</sup> mouse model confirms the pathological role of MSI2 expression levels as an atrophy-associated component that impacts the characteristic muscle dysfunction symptoms in DM1 patients.</p></div>\",\"PeriodicalId\":8934,\"journal\":{\"name\":\"Biomedical Journal\",\"volume\":\"47 4\",\"pages\":\"Article 100667\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S231941702300104X/pdfft?md5=1be53c3ab977b1e60a3e8df7bda4edd9&pid=1-s2.0-S231941702300104X-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biomedical Journal\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S231941702300104X\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomedical Journal","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S231941702300104X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Msi2 enhances muscle dysfunction in a myotonic dystrophy type 1 mouse model
Background
Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the 3′ untranslated region of the DM1 protein kinase gene. Characteristic degenerative muscle symptoms include myotonia, atrophy, and weakness. We previously proposed an Musashi homolog 2 (MSI2)>miR-7>autophagy axis whereby MSI2 overexpression repressed miR-7 biogenesis that subsequently de-repressed muscle catabolism through excessive autophagy. Because the DM1 HSALR mouse model expressing expanded CUG repeats shows weak muscle-wasting phenotypes, we hypothesized that MSI2 overexpression was sufficient to promote muscle dysfunction in vivo.
Methods
By means of recombinant AAV murine MSI2 was overexpressed in neonates HSALR mice skeletal muscle to induce DM1-like phenotypes.
Results
Sustained overexpression of the murine MSI2 protein in HSALR neonates induced autophagic flux and expression of critical autophagy proteins, increased central nuclei and reduced myofibers area, and weakened muscle strength. Importantly, these changes were independent of MBNL1, MBNL2, and Celf1 protein levels, which remained unchanged upon Msi2 overexpression.
Conclusions
Globally, molecular, histological, and functional data from these experiments in the HSALR mouse model confirms the pathological role of MSI2 expression levels as an atrophy-associated component that impacts the characteristic muscle dysfunction symptoms in DM1 patients.
期刊介绍:
Biomedical Journal publishes 6 peer-reviewed issues per year in all fields of clinical and biomedical sciences for an internationally diverse authorship. Unlike most open access journals, which are free to readers but not authors, Biomedical Journal does not charge for subscription, submission, processing or publication of manuscripts, nor for color reproduction of photographs.
Clinical studies, accounts of clinical trials, biomarker studies, and characterization of human pathogens are within the scope of the journal, as well as basic studies in model species such as Escherichia coli, Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus revealing the function of molecules, cells, and tissues relevant for human health. However, articles on other species can be published if they contribute to our understanding of basic mechanisms of biology.
A highly-cited international editorial board assures timely publication of manuscripts. Reviews on recent progress in biomedical sciences are commissioned by the editors.