{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:48:07Z","timestamp":1785415687414,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2026-25480711"],"award-info":[{"award-number":["RS-2026-25480711"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2026-25480711"],"award-info":[{"award-number":["RS-2026-25480711"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Molecule Interacting with CasL 1 (MICAL1) is a flavoprotein monooxygenase that promotes filamentous actin (F-actin) depolymerization. Transcriptomic studies have linked MICAL1 downregulation to skeletal muscle atrophy and muscular dystrophy, yet its functional contribution to myogenesis remains unexplored. We found that MICAL1 protein increased progressively during myogenic differentiation of C2C12 cells, reaching a maximum on day 5 in parallel with myosin heavy chain (MyHC). siRNA-mediated MICAL1 silencing produced an ~1.7-fold accumulation of F-actin, while total \u03b2-actin protein remained unchanged, indicating a shift in the G-\/F-actin equilibrium toward polymerization rather than altered actin expression. The accumulated F-actin reduced YAP1 phosphorylation, promoted its nuclear translocation, and increased the expression of the YAP1 target gene CTGF. MICAL1 depletion also enhanced myoblast proliferation: EdU incorporation and cell viability increased, and PCNA, CCNB1, and CCND1 protein expression was upregulated, while the cell cycle distribution shifted toward the G2\/M phase, with a reciprocal loss in G0\/G1. Concurrently, MICAL1 knockdown suppressed MyoD, Myogenin, and MyHC throughout differentiation and severely impaired myotube formation, with reductions in the fusion index, myotube area, and length. We conclude that MICAL1 is required for the proliferation-to-differentiation switch in myoblasts and that its activity restrains F-actin-driven YAP1 signaling to permit timely myogenic commitment. MICAL1 may therefore represent a candidate for further investigation in muscle-wasting diseases.<\/jats:p>","DOI":"10.3390\/ijms27146505","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T10:48:28Z","timestamp":1784717308000},"page":"6505","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MICAL1 Contributes to Myogenic Differentiation by Modulating Actin Remodeling and YAP1 Nuclear Localization in C2C12 Myoblasts"],"prefix":"10.3390","volume":"27","author":[{"given":"Thanh Huu Phan","family":"Ngo","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quoc Kiet","family":"Ly","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5181-2135","authenticated-orcid":false,"given":"Wan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea"},{"name":"Section of Molecular and Cellular Medicine, Medical Institute of Dongguk University, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/B978-0-323-98818-6.00013-3","article-title":"Skeletal muscle structure, physiology, and function","volume":"195","author":"Brooks","year":"2023","journal-title":"Handb. Clin. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.1111\/febs.12253","article-title":"Mechanisms regulating skeletal muscle growth and atrophy","volume":"280","author":"Schiaffino","year":"2013","journal-title":"FEBS J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/s41467-020-20123-1","article-title":"Mechanisms of muscle atrophy and hypertrophy: Implications in health and disease","volume":"12","author":"Sartori","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1242\/dev.151035","article-title":"Making muscle: Skeletal myogenesis in vivo and in vitro","volume":"144","author":"Chal","year":"2017","journal-title":"Development"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e649","DOI":"10.1002\/mco2.649","article-title":"Skeletal muscle: Molecular structure, myogenesis, biological functions, and diseases","volume":"5","author":"Feng","year":"2024","journal-title":"MedComm"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.devcel.2013.12.020","article-title":"Gene regulatory networks and transcriptional mechanisms that control myogenesis","volume":"28","author":"Buckingham","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.tibs.2019.11.003","article-title":"The cytoskeleton as regulator of cell signaling pathways","volume":"45","author":"Moujaber","year":"2020","journal-title":"Trends Biochem. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"452","DOI":"10.4161\/cib.2.5.9158","article-title":"Cytoskeletal remodeling during myotube assembly and guidance: Coordinating the actin and microtubule networks","volume":"2","author":"Guerin","year":"2009","journal-title":"Commun. Integr. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"a018226","DOI":"10.1101\/cshperspect.a018226","article-title":"Actin and Actin-Binding Proteins","volume":"8","author":"Pollard","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1242\/jcs.047597","article-title":"Nap1-mediated actin remodeling is essential for mammalian myoblast fusion","volume":"122","author":"Nowak","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1242\/jcs.039255","article-title":"Microtubule plus-end binding protein EB1 is necessary for muscle cell differentiation, elongation and fusion","volume":"122","author":"Zhang","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nguyen, M.T., Dash, R., Jeong, K., and Lee, W. (2023). Role of actin-binding proteins in skeletal myogenesis. Cells, 12.","DOI":"10.3390\/cells12212523"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"151241","DOI":"10.1016\/j.ejcb.2022.151241","article-title":"Role of actin-binding proteins in the regulation of cellular mechanics","volume":"101","author":"Vakhrusheva","year":"2022","journal-title":"Eur. J. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.bbrc.2022.02.021","article-title":"Twinfilin-1 is an essential regulator of myogenic differentiation through the modulation of YAP in C2C12 myoblasts","volume":"599","author":"Nguyen","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.bbrc.2020.11.016","article-title":"CFL2 is an essential mediator for myogenic differentiation in C2C12 myoblasts","volume":"533","author":"Nguyen","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/S0092-8674(02)00794-8","article-title":"MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion","volume":"109","author":"Terman","year":"2002","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1038\/ncb3390","article-title":"F-actin dismantling through a redox-driven synergy between Mical and cofilin","volume":"18","author":"Grintsevich","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nature08724","article-title":"Mical links semaphorins to F-actin disassembly","volume":"463","author":"Hung","year":"2010","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14528","DOI":"10.1038\/ncomms14528","article-title":"Oxidation of F-actin controls the terminal steps of cytokinesis","volume":"8","author":"Fremont","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1152\/japplphysiol.01055.2004","article-title":"Transcriptional profile of a myotube starvation model of atrophy","volume":"98","author":"Stevenson","year":"2005","journal-title":"J. Appl. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Screen, M., Raheem, O., Holmlund-Hampf, J., Jonson, P.H., Huovinen, S., Hackman, P., and Udd, B. (2014). Gene expression profiling in tibial muscular dystrophy reveals unfolded protein response and altered autophagy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090819"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1002\/jcsm.12552","article-title":"Recent developments in the field of cachexia, sarcopenia, and muscle wasting: Highlights from the 12th Cachexia Conference","volume":"11","author":"Ebner","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1249\/JES.0000000000000142","article-title":"The Hippo signaling pathway in the regulation of skeletal muscle mass and function","volume":"46","author":"Watt","year":"2018","journal-title":"Exerc. Sport Sci. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Fischer, M., Rikeit, P., Knaus, P., and Coirault, C. (2016). YAP-mediated mechanotransduction in skeletal muscle. Front. Physiol., 7.","DOI":"10.3389\/fphys.2016.00041"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10137","article-title":"Role of YAP\/TAZ in mechanotransduction","volume":"474","author":"Dupont","year":"2011","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.cell.2013.07.042","article-title":"A Mechanical Checkpoint Controls Multicellular Growth through YAP\/TAZ Regulation by Actin-Processing Factors","volume":"154","author":"Aragona","year":"2013","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.yexcr.2015.10.034","article-title":"Role of YAP\/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction","volume":"343","author":"Dupont","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nrm.2017.87","article-title":"Mechanobiology of YAP and TAZ in physiology and disease","volume":"18","author":"Panciera","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1152\/physrev.00005.2014","article-title":"The biology of YAP\/TAZ: Hippo signaling and beyond","volume":"94","author":"Piccolo","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6048","DOI":"10.1038\/ncomms7048","article-title":"The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size","volume":"6","author":"Watt","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.bbrc.2010.02.034","article-title":"Yap is a novel regulator of C2C12 myogenesis","volume":"393","author":"Watt","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6009","DOI":"10.1242\/jcs.109546","article-title":"The Hippo pathway member Yap plays a key role in influencing fate decisions in muscle satellite cells","volume":"125","author":"Judson","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.ccr.2014.05.029","article-title":"The Hippo transducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation","volume":"26","author":"Tremblay","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1128\/MCB.01389-10","article-title":"MICAL-1 is a negative regulator of MST-NDR kinase signaling and apoptosis","volume":"31","author":"Zhou","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.molcel.2008.09.009","article-title":"MyoD targets TAF3\/TRF3 to activate myogenin transcription","volume":"32","author":"Deato","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7375","DOI":"10.1038\/s41467-025-62487-2","article-title":"F-actin disassembly by the oxidoreductase MICAL1 promotes mechano-dependent VWF-GPIb\u03b1 interaction in platelets","volume":"16","author":"Solarz","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gad.274027.115","article-title":"Mechanisms of Hippo pathway regulation","volume":"30","author":"Meng","year":"2016","journal-title":"Genes Dev."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Nguyen, M.T., Ly, Q.K., Ngo, T.H.P., and Lee, W. (2025). Calponin 3 Regulates Myoblast Proliferation and Differentiation Through Actin Cytoskeleton Remodeling and YAP1-Mediated Signaling in Myoblasts. Cells, 14.","DOI":"10.3390\/cells14020142"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5117","DOI":"10.1038\/onc.2012.5","article-title":"YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes","volume":"31","author":"Mizuno","year":"2012","journal-title":"Oncogene"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.1007\/s12013-025-01668-8","article-title":"MICAL1 Mediates TGF-\u03b21-Induced Epithelial-to-Mesenchymal Transition and Metastasis of Hepatocellular Carcinoma by Activating Smad2\/3","volume":"83","author":"Zhuang","year":"2025","journal-title":"Cell Biochem. Biophys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1007\/s13353-024-00919-3","article-title":"Prognostic biomarker MICAL2 and associates with proliferation, migration and immune infiltration in pancreatic adenocarcinoma","volume":"66","author":"Yang","year":"2025","journal-title":"J. Appl. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6505\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T10:54:19Z","timestamp":1784717659000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":41,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146505"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146505","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]}}}