{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:19:08Z","timestamp":1774646348574,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T00:00:00Z","timestamp":1702339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Limb girdle muscular dystrophies (LGMDs) are a group of genetically inherited neuromuscular diseases with a very variable clinical presentation and overlapping traits. Over the last few years there has been an increasing interest in the use of non-invasive circulating biomarkers to monitor disease progression and to evaluate the efficacy of therapeutic approaches. Our aim was to identify the miRNA signature with potential value for LGMD patient screening and stratification. Using miRCURY LNA miRNA qPCR Serum\/Plasma Panel, we analyzed 179 miRNAs from 16 patients, divided in four pools based on their genetic diagnosis, and from healthy controls. The miRNAs analysis showed a total of 107 dysregulated miRNAs in LGMD patients when compared to the healthy controls. After filtering via skeletal tissue expression and gene\/pathways target analysis, the number of dysregulated miRNAs drastically reduced. Six selected miRNAs\u2014let-7f-5p (in LGMDR1), miR-20a-5p (in LGMDR2), miR-130b-5p, miR-378a-5p (both in LGMDR3), miR-376c-3p and miR-382-5p (both in LGMDR4)\u2014whose expression was significantly lower compared to controls in the different LGMD pools, were further investigated. The bioinformatic analysis of the target genes in each selected miRNA revealed ECM\u2013receptor interaction and TGF-beta signaling as the most involved pathways. The correlation analysis showed a good correlation of let-7f-5p with fibrosis and with the cross sectional area of type I and type II fibers, while miR-130b-5p showed a good correlation with the age of onset of the disease. The receiver operating characteristic curves showed how single miRNAs were able to discriminate a specific group of LGMD patients and how the combination of six miRNAs was able to discriminate LGMD patients from controls.<\/jats:p>","DOI":"10.3390\/ijms242417402","type":"journal-article","created":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T09:15:33Z","timestamp":1702372533000},"page":"17402","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Profiling of 179 miRNA Expression in Serum from Limb Girdle Muscular Dystrophy Patients and Healthy Controls"],"prefix":"10.3390","volume":"24","author":[{"given":"Francesca","family":"Magri","sequence":"first","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4607-8084","authenticated-orcid":false,"given":"Laura","family":"Napoli","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9293-6823","authenticated-orcid":false,"given":"Michela","family":"Ripolone","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizia","family":"Ciscato","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Moggio","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5425-969X","authenticated-orcid":false,"given":"Stefania","family":"Corti","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo Pietro","family":"Comi","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4593-4977","authenticated-orcid":false,"given":"Monica","family":"Sciacco","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Zanotti","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1007\/s10930-021-10006-9","article-title":"A Journey with LGMD: From Protein Abnormalities to Patient Impact","volume":"40","author":"Georganopoulou","year":"2021","journal-title":"Protein J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.nmd.2008.09.015","article-title":"A new phenotype of dysferlinopathy with congenital onset","volume":"19","author":"Paradas","year":"2009","journal-title":"Neuromuscul. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/mus.27222","article-title":"Elevation of fast but not slow troponin I in the circulation of patients with Becker and Duchenne muscular dystrophy","volume":"64","author":"Barthel","year":"2021","journal-title":"Muscle Nerve"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.nmd.2011.05.011","article-title":"Serum matrix metalloproteinase-9 (MMP-9) as a biomarker for monitoring disease progression in Duchenne muscular dystrophy (DMD)","volume":"21","author":"Nadarajah","year":"2011","journal-title":"Neuromuscul. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3233\/JND-140066","article-title":"Muscle-Derived Proteins as Serum Biomarkers for Monitoring Disease Progression in Three Forms of Muscular Dystrophy","volume":"2","author":"Burch","year":"2015","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4916","DOI":"10.1093\/hmg\/ddv214","article-title":"Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies","volume":"24","author":"Rouillon","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1111\/jcmm.13450","article-title":"miRNA in spinal muscular atrophy pathogenesis and therapy","volume":"22","author":"Magri","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Fonseca, \u00c1., Martin-Jimenez, C., Barreto, G.E., Pach\u00f3n, A.F.A., and Gonz\u00e1lez, J. (2021). The Emerging Role of Long Non-Coding RNAs and MicroRNAs in Neurodegenerative Diseases: A Perspective of Machine Learning. Biomolecules, 11.","DOI":"10.3390\/biom11081132"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gentile, G., Morello, G., La Cognata, V., Guarnaccia, M., Conforti, F.L., and Cavallaro, S. (2022). Dysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases. J. Pers. Med., 12.","DOI":"10.3390\/jpm12050770"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/nature03702","article-title":"MicroRNA expression profiles classify human cancers","volume":"435","author":"Lu","year":"2005","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41416-021-01672-8","article-title":"Non-coding RNAs as liquid biopsy biomarkers in cancer","volume":"126","author":"Toden","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.molimm.2022.04.017","article-title":"Allergic inflammation in lungs and nasal epithelium of rat model is regulated by tissue-specific miRNA expression","volume":"147","author":"Szczepankiewicz","year":"2022","journal-title":"Mol. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"863238","DOI":"10.3389\/fcvm.2022.863238","article-title":"Cardiac Remodeling After Myocardial Infarction: Functional Contribution of microRNAs to Inflammation and Fibrosis","volume":"9","author":"Varzideh","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1016\/j.bbadis.2015.04.013","article-title":"Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy","volume":"1852","author":"Zanotti","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Arrighi, N., Moratal, C., Savary, G., Fassy, J., Nottet, N., Pons, N., Cl\u00e9ment, N., Fellah, S., Larrue, R., and Magnone, V. (2021). The FibromiR miR-214-3p Is Upregulated in Duchenne Muscular Dystrophy and Promotes Differentiation of Human Fibro-Adipogenic Muscle Progenitors. Cells, 10.","DOI":"10.3390\/cells10071832"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ar\u00e1nega, A.E., Lozano-Velasco, E., Rodriguez-Outeiri\u00f1o, L., Ram\u00edrez de Acu\u00f1a, F., Franco, D., and Hern\u00e1ndez-Torres, F. (2021). MiRNAs and Muscle Regeneration: Therapeutic Targets in Duchenne Muscular Dystrophy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084236"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17016","DOI":"10.1073\/pnas.0708115104","article-title":"Distinctive patterns of microRNA expression in primary muscular disorders","volume":"104","author":"Eisenberg","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Vignier, N., Amor, F., Fogel, P., Duvallet, A., Poupiot, J., Charrier, S., Arock, M., Montus, M., Nelson, I., and Richard, I. (2013). Distinctive serum miRNA profile in mouse models of striated muscular pathologies. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055281"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zaharieva, I.T., Calissano, M., Scoto, M., Preston, M., Cirak, S., Feng, L., Collins, J., Kole, R., Guglieri, M., and Straub, V. (2013). Dystromirs as serum biomarkers for monitoring the disease severity in Duchenne muscular Dystrophy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080263"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s10974-019-09555-5","article-title":"Influence of microRNAs and exosomes in muscle health and diseases","volume":"41","author":"Lam","year":"2020","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4678","DOI":"10.1111\/jcmm.17462","article-title":"MicroRNAs as serum biomarkers in Becker muscular dystrophy","volume":"26","author":"Gagliardi","year":"2022","journal-title":"J. Cell Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.rmed.2006.01.001","article-title":"Reference values for the 6-min walk test in healthy subjects 20-50 years old","volume":"100","author":"Chetta","year":"2006","journal-title":"Respir. Med."},{"key":"ref_23","first-page":"98","article-title":"Expression of Let-7 family microRNAs in skin correlates negatively with severity of pulmonary hypertension in patients with systemic scleroderma","volume":"8","author":"Izumiya","year":"2015","journal-title":"Int. J. Cardiol. Heart Vasc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s12079-020-00553-8","article-title":"HIF-hypoxia signaling in skeletal muscle physiology and fibrosis","volume":"14","author":"Rebolledo","year":"2020","journal-title":"J. Cell Commun. Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"281756","DOI":"10.1155\/2015\/281756","article-title":"The Role of miR-378a in Metabolism, Angiogenesis, and Muscle Biology","volume":"2015","author":"Krist","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1080\/15476286.2016.1239008","article-title":"miR-378a-3p promotes differentiation and inhibits proliferation of myoblasts by targeting HDAC4 in skeletal muscle development","volume":"13","author":"Wei","year":"2016","journal-title":"RNA Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1182\/blood-2012-02-408252","article-title":"Induction of IL-4Ralpha-dependent microRNAs identifies PI3K\/Akt signaling as essential for IL-4-driven murine macrophage proliferation in vivo","volume":"120","author":"Ruckerl","year":"2012","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"F1390","DOI":"10.1152\/ajprenal.00458.2014","article-title":"Repression of let-7 by transforming growth factor-\u03b21-induced Lin28 upregulates collagen expression in glomerular mesangial cells under diabetic conditions","volume":"307","author":"Park","year":"2014","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1164\/rccm.200911-1698OC","article-title":"Inhibition and role of let-7d in idiopathic pulmonary fibrosis","volume":"182","author":"Pandit","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1681\/ASN.2012060550","article-title":"Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGF\u03b2R1","volume":"24","author":"Brennan","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/ki.2013.372","article-title":"Transforming growth factor-\u03b21-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b","volume":"85","author":"Wang","year":"2014","journal-title":"Kidney Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/onc.2010.485","article-title":"Collagen regulation of let-7 in pancreatic cancer involves TGF-\u03b21-mediated membrane type 1-matrix metalloproteinase expression","volume":"30","author":"Strouch","year":"2011","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e13425","DOI":"10.1111\/eci.13425","article-title":"Let-7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL-6","volume":"51","author":"Di","year":"2021","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"24986","DOI":"10.1074\/jbc.M115.659375","article-title":"Genome-wide Mechanosensitive MicroRNA (MechanomiR) Screen Uncovers Dysregulation of Their Regulatory Networks in the mdm Mouse Model of Muscular Dystrophy","volume":"290","author":"Mohamed","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s00441-013-1601-2","article-title":"Duchenne muscular dystrophy fibroblast nodules: A cell-based assay for screening anti-fibrotic agents","volume":"352","author":"Zanotti","year":"2013","journal-title":"Cell Tissue Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3389\/fonc.2020.00107","article-title":"Mir-20a-5p\/tgfbr2 axis affects pro-inflammatory macrophages and aggravates liver fibrosis","volume":"10","author":"Fu","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1212\/WNL.56.11.1472","article-title":"The earliest pathologic alterations in dysferlinopathy","volume":"56","author":"Selcen","year":"2001","journal-title":"Neurology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e22580","DOI":"10.1096\/fj.202200228RRRRR","article-title":"Transforming growth factor-\u03b2 receptor type 2 is required for heparin-binding protein-induced acute lung injury and vascular leakage for transforming growth factor-\u03b2\/Smad\/Rho signaling pathway activation","volume":"36","author":"Liu","year":"2022","journal-title":"FASEB J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1002\/jcp.29987","article-title":"MiR-130b-3p regulates M1 macrophage polarization via targeting IRF1","volume":"236","author":"Guo","year":"2021","journal-title":"J. Cell Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6601","DOI":"10.1002\/jcp.27401","article-title":"MicroRNA-382 silencing induces a mitonuclear protein imbalance and activates the mitochondrial unfolded protein response in muscle cells","volume":"234","author":"Dahlmans","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.1016\/j.ajpath.2020.06.011","article-title":"The Common miRNA Signatures Associated with Mitochondrial Dysfunction in Different Muscular Dystrophies","volume":"190","author":"Yuzbasioglu","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1002\/jcsm.12578","article-title":"A subset of microRNAs in the Dlk1-Dio3 cluster regulates age-associated muscle atrophy by targeting Atrogin-1","volume":"11","author":"Shin","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ahmad, S.S., Ahmad, K., Lee, E.J., Lee, Y.H., and Choi, I. (2020). Implications of Insulin-Like Growth Factor-1 in Skeletal Muscle and Various Diseases. Cells, 9.","DOI":"10.3390\/cells9081773"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1186\/s13023-022-02603-3","article-title":"Identification of circulating miRNAs differentially expressed in patients with Limb-girdle, Duchenne or facioscapulohumeral muscular dystrophies","volume":"17","author":"Bas","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40478-022-01354-3","article-title":"Muscle histological changes in a large cohort of patients affected with Becker muscular dystrophy","volume":"10","author":"Ripolone","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1093\/nar\/gkw116","article-title":"Distribution of miRNA expression across human tissues","volume":"44","author":"Ludwig","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"W191","DOI":"10.1093\/nar\/gkz369","article-title":"g:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update)","volume":"47","author":"Raudvere","year":"2019","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17402\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:37:25Z","timestamp":1760132245000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,12]]},"references-count":48,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242417402"],"URL":"https:\/\/doi.org\/10.3390\/ijms242417402","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,12]]}}}