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Dysregulated muscle repair and regeneration gene co\u2010expression networks are present in critical illness survivors with persistent muscle wasting and weakness. We aimed to identify microRNAs (miRs) regulating the gene networks and determine their role in the self\u2010renewal of muscle in ICU survivors.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Muscle whole\u2010transcriptome expression was assessed with microarrays in banked quadriceps biopsies obtained at 7\u00a0days and 6\u00a0months post\u2010ICU discharge from critically ill patients (\n n<\/jats:italic>\n \u00a0=\u00a015) in the RECOVER programme and healthy individuals (\n n<\/jats:italic>\n \u00a0=\u00a08). We conducted an integrated miR\u2013messenger RNA analysis to identify miR\/gene pairs associated with muscle recovery post\u2010critical illness and evaluated their impact on myoblast proliferation and differentiation in human AB1167 and murine C2C12 cell lines\n in vitro<\/jats:italic>\n . Select target genes were validated with quantitative PCR.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Twenty\u2010two miRs were predicted to regulate the Day 7 post\u2010ICU muscle transcriptome vs. controls. Thirty per cent of all differentially expressed genes shared a 3'UTR regulatory sequence for miR\u2010424\u20103p\/5p, which was 10\u2010fold down\u2010regulated in patients (\n P<\/jats:italic>\n \u00a0<\u00a00.001) and correlated with quadriceps size (\n R<\/jats:italic>\n \u00a0=\u00a00.86,\n P<\/jats:italic>\n \u00a0<\u00a00.001), strength (\n R<\/jats:italic>\n \u00a0=\u00a00.75,\n P<\/jats:italic>\n \u00a0=\u00a00.007), and physical function (Functional Independence Measures motor subscore,\n R<\/jats:italic>\n \u00a0=\u00a00.92,\n P<\/jats:italic>\n \u00a0<\u00a00.001) suggesting its potential role as a master regulator of early recovery of muscle mass and strength following ICU discharge. Network analysis demonstrated enrichment for cellular respiration and muscle fate commitment\/development related genes. At 6\u00a0months post\u2010ICU discharge, a 14\u2010miR expression signature, including miRs\u2010490\u20103p and \u2010744\u20105p, identified patients with muscle mass recovery vs. those with sustained atrophy. Constitutive overexpression of the novel miR\u2010490\u20103p significantly inhibited AB1167 and C2C12 myoblast proliferation (cell count AB1167 miR\u2010490\u20103p mimic or scrambled\u2010miR transfected myoblasts 7926\u00a0\u00b1\u00a04060 vs. 14\u00a0159\u00a0\u00b1\u00a03515 respectively,\n P<\/jats:italic>\n \u00a0=\u00a00.006; proportion Ki67\u2010positive nuclei AB1167 miR\u2010490\u20103p mimic or scrambled\u2010miR transfected myoblasts 0.38\u00a0\u00b1\u00a00.07 vs. 0.54\u00a0\u00b1\u00a00.06 respectively,\n P<\/jats:italic>\n \u00a0<\u00a00.001; proliferating cell nuclear antigen expression AB1167 miR\u2010490\u20103p mimic or scrambled\u2010miR transfected myoblasts 11.48\u00a0\u00b1\u00a01.97 vs. 16.75\u00a0\u00b1\u00a01.19 respectively,\n P<\/jats:italic>\n \u00a0=\u00a00.040). Constitutive overexpression of miR\u2010744\u20105p, a known regulator of myogenesis, significantly inhibited AB1167 and C2C12 myoblast differentiation (fusion index AB1167 miR\u2010744\u20105p mimic or scrambled\u2010miR transfected myoblasts 8.31\u00a0\u00b1\u00a07.00% vs. 40.29\u00a0\u00b1\u00a09.37% respectively,\n P<\/jats:italic>\n \u00a0<\u00a00.001; myosin heavy chain expression miR\u2010744\u20105p mimic or scrambled\u2010miR transfected myoblasts 0.92\u00a0\u00b1\u00a00.39 vs. 13.53\u00a0\u00b1\u00a05.5 respectively,\n P<\/jats:italic>\n \u00a0=\u00a00.01).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Combined functional transcriptomics identified 36 miRs including miRs\u2010424\u20103p\/5p, \u2010490\u20103p, and \u2010744\u20105p as potential regulators of gene networks associated with recovery of muscle mass and strength following critical illness. MiR\u2010490\u20103p is identified as a novel regulator of myogenesis.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.12903","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T02:48:59Z","timestamp":1643424539000},"page":"1262-1276","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["MicroRNA regulatory networks associated with abnormal muscle repair in survivors of critical illness"],"prefix":"10.1002","volume":"13","author":[{"given":"Christopher J.","family":"Walsh","sequence":"first","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St Michael's Hospital Unity Health Toronto Toronto ON Canada"},{"name":"Institute of Medical Science University of Toronto Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Escudero King","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical 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