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Glucocorticoid excess sustains muscle atrophy and weakness, while muscle-specific microRNAs (myomiRs) level changes were associated with muscle organization and function perturbation. The aim of the current study is to explore changes in circulating myomiRs in CS patients compared to healthy controls and their involvement in IGFI\/PI3K\/Akt\/mTOR pathway regulation in skeletal muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>C2C12, mouse myocytes, were exposed to hydrocortisone (HC), and atrophy-related gene expression was investigated by RT-qPCR, WB and IF to assess HC-mediated atrophic signalling. miRNAs were evaluated in HC-treated C2C12 by PCR Arrays. MyomiRs significantly overexpressed in C2C12 were investigated in 37 CS patients and 24 healthy controls serum by RT-qPCR. The anti-anabolic role of circulating miRNAs significantly upregulated in CS patients was explored in C2C12 by investigating the IGFI\/PI3K\/Akt\/mTOR pathway regulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HC induced higher expression of atrophy-related genes, miR-133a-3p, miR-122-5p and miR-200b-3p in C2C12 compared to untreated cells. Conversely, the anabolic IGFI\/PI3K\/Akt\/mTOR signalling was reduced and this effect was mediated by miR-133a-3p. In CS patients miR-133a-3p and miR-200b-3p revealed higher circulating levels (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, respectively) compared to controls. ROC curves for miR-133a-3p (AUC 0.823,<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and miR-200b-3p (AUC 0.850,<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) demonstrated that both myomiRs represent potential biomarkers to discriminate between CS and healthy subjects. Pearson\u2019s correlation analysis revealed that circulating levels of miR-133a-3p are directly correlated with 24\u00a0h urinary-free cortisol level (<jats:italic>r<\/jats:italic>\u2009=\u20090.468,<jats:italic>p<\/jats:italic>\u2009=\u20090.004) in CS patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>HC induces atrophic signals by miR-133a-3p overexpression in mouse myocytes and humans. Circulating miR-133a-3p is promising biomarkers of hypercortisolism.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s40618-023-02184-3","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T12:02:35Z","timestamp":1694174555000},"page":"655-669","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Circulating myomiRNAs as biomarkers in patients with Cushing\u2019s syndrome"],"prefix":"10.1007","volume":"47","author":[{"given":"C.","family":"Pivonello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Patalano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Simeoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Mont\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Negri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Amatrudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Di Paola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Larocca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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A.C. has been Principal Investigator of Research Studies for Novartis, Ipsen, Pfizer, Lilly, Merck and Novo Nordisk; consultant for Novartis, Ipsen, and Pfizer and received honoraria from Novartis, Ipsen and Pfizer. The remaining authors have nothing to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was performed in accordance with the ethical standards of the Declaration of Helsinki, and it was approved by the Ethics Committee of the University Federico II of Naples (Italy) (EC Prot. 215\/18). Healthy volunteers were recruited from staff and the University Federico II of Naples (Italy) faculty population. Healthy volunteers did not have any complaints regarding their health and did not have signs or symptoms indicative of CS after an endocrinological examination.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All enrolled subjects provided signed informed consent.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}