ECE2021 Oral Communications Young Investigator Awards (12 abstracts)
Circulating myomiRNAs as biomarkers of Cushing’s syndrome
Claudia Pivonello 1 , Roberta Patalano 2 , Mariarosaria Negri 1 , Tatiana Montò 1 , Feliciana Amatrudo 1 , Nicola Di Paola 1 , Marina Iacono 1 , Chiara Simeoli 1 , Rosario Ferrigno 1 , Domenico Solari 3 , Cristina De Angelis 1 , Renata Simona Auriemma 1 , Paolo Cappabianca 3 , Annamaria Colao 1 & Rosario Pivonello 1
1Federico II University, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Naples, Italy; 2Federico II University, Dipartimento di Sanità Pubblica, Naples, Italy; 3Federico II University, Department of Neuroscience, Division of Neurosurgery, Reproductive and Odontostomatological Sciences, Naples, Italy
Cushing’s syndrome (CS) is a rare endocrine disease caused by a chronic exposure to endogenous cortisol or exogenous glucocorticoids (GCs). Among multiple comorbidities, impairment of skeletal muscle mass and strength affects 40–70% of patients with active CS and persist even after long-term disease remission. In pathological conditions, GCs excess sustain muscle atrophy and weakness affecting type II muscle fibers. Muscle-specific microRNAs, defined myomiRs, are involved in myoblast proliferation, differentiation and regeneration, and changes in myomiR levels were reported in several pathological conditions associated with muscle organization and function perturbations. The current study aims to explore changes in circulating myomiRs in patients with CS, characterized by muscle atrophy and weakness compared to heathy controls. To focus the clinical study on a specific myomiRs subset, C2C12, mouse myoblast cell line, differentiated into myocytes, was exposed to 1.4 × 10–6 M of hydrocortisone (HC), resembling high cortisol serum level (500 ng/ml) observed in CS patients, for 4, 6, 8 and 12 hrs and gene and protein expression of the atrophy-related genes Atrogin and Murf were investigated by RT-qPCR, Western Blot and immunofluorescence to assess the HC-mediated atrophic signaling. The myomiRs levels were evaluated in treated C2C12 and controls by miScript miRNA PCR array. Circulating myomiRs significantly overexpressed in HC-treated C2C12 were then investigated by RT-qPCR in 33 patients affected by CS and 12 sex–and age-matched healthy controls. HC induced muscle atrophic signals significantly increasing Atrogin and Murf gene and protein expression and a concomitant higher expression of miR-133a-3p, miR-122–5p and miR-200b-3p in C2C12 after 12 hrs of treatment. The evaluation of these myomiRs in CS patients revealed higher circulating levels of miR-133a-3p (P < 0.0001), miR-122–5p (P = 0.0135) and miR-200b-3p (P < 0.0001) compared to controls. ROC curves for miR-133a-3p (AUC 0.866 (95% CI 0.756–0.976, P = 0.0002) and miR-200b-3p (AUC 0.976 (95% CI 0.930–1.023, P < 0.0001) demonstrated that both myomiRs represent potential biomarkers to discriminate between CS and healthy subjects. Interestingly, linear regression analysis revealed that circulating levels of miR-133a-3p are directly correlated with 24h urinary free cortisol level (r = 0.428, P = 0.026) in the CS patients. In conclusion, this study confirmed that HC induces atrophic signals and myomiR overexpression in mouse muscle cells, and in humans, circulating miR-200b-3p and mainly miR-133a-3p levels are promising molecular markers of hypercortisolism.
Volume 73
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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