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Emery-Dreifuss muscular dystrophy (EDMD) is mainly inherited in an X-linked (EDMD1), and autosomal dominant (EDMD2) manner, ranging from early onset severe-childhood to slowly progressive adulthood phenotypes. Common features are joint contractures, humero-peroneal muscle weakness with later scapular-pelvic girdle muscles involvement, and cardiopathy. The pathogenic and clinical variability makes the correct diagnostic framing often not initially clear, hence, combining clinical evaluation with serum biomarkers would enable conclusive early diagnosis. Cardiac and skeletal muscles are enriched in a group of specific microRNAs (miRNAs), called myomiRs (miR-1, miR-133a, miR-133b, miR-206), which have a crucial role in myogenic processes and muscle homeostasis as they target several muscle-related genes triggering and sustaining muscle atrophy. Here, we investigated for the first time the involvement and potential clinical use in EDMDs of myomiRs and miR-21, a critical fibrosis promoter. By qRT-PCR, we analysed myomiR and miR-21 expression in EDMD1 patient-derived myoblasts and tenocytes, and in the respective CRISPR-corrected cells. An up-regulation of miR-206, miR-133a, miR-133b and miR-1 specifically in myoblasts after efficient correction of the genotype, and the down-regulation of miR-21 both in corrected tenocytes and myoblasts, were observed. Further, we examined myomiR and miR-21 expression in serum of 21 adult EDMD2 patients, and 21 age-matched healthy controls. We demonstrated a significant serum miR-206 and miR-21 up-regulation in EDMD2 patients compared to controls (p<0.0001). We then extended the miRNA analysis to miR-34a, -34b and -34c, previously associated with Progeria, one of the most severe laminopathies, as senescence/profibrotic markers and found higher miR-34a and -34c levels in EDMD2 patients' sera than controls (p<0.001). Our findings point out myomiRs, miR-21, miR-34a, and -34c as potential diagnostic markers and therapeutic targets for EDMDs. [ABSTRACT FROM AUTHOR]