Collagen VI is the main extracellular matrix (ECM) protein synthesized and secreted mainly by fibroblasts that forms a structurally network of microfilaments. Collagen VI binds several cell surface receptors and ECM components, suggesting that collagen VI is an important mechanical link between muscle cells and surrounding ECM. [1] Mutations related to COL6A1, COL6A2 and COL6A3 genes encoding for the three main collagen VI chains, cause the collagen VI-related myopathy, a specific subtype of congenital muscular dystrophy (CMD). In particular Ullrich congenital muscular dystrophy (UCMD) is a severe form characterized by progressive muscle wasting leading to loss of ambulation around ten years of age and respiratory problems in late childhood or young adulthood. Bethlem Miopathy (BM) is a mild-form characterized by a slow course usually without respiratory symptoms where around 50% of patients lose ambulation in the fifth decade. [2] Being the genetic test aimed to find mutations in COL6A genes expensive and time consuming mainly because the large size of the three genes, (106 coding exons in total [2]) the diagnosis of collagen VI-related myopathies is based on the clinical signs assessment coupled to the muscular biopsy which is useful to highlight any dystrophic or myopathic changes in the muscle fibers of the patient. The aim of the present work has been to identify a panel of miRNAs significantly dysregulated in col6a1-/- mice, the animal model of Bethlem myopathy and Ullrich congenital muscular dystrophy. miRNAs represent an ideal biomarker because they are easy to detect, well preserved in serum and non invasive. The findings of this work can be translated, in a further step, in a cohort of affected patients in order to become a powerful tool for the diagnosis and the follow-up of collagen VI-related myopathy. Research projects aimed to link the differential miRNA expression to pathological conditions are increasing and this suggests how miRNAs could be used as powerful tool to track disease related changes on a large scale in the forthcoming years. In order to identify differentially expressed miRNAs in knock-out col6a1-/- (KO) mice serum, a miRNAs expression profiling analysis by SYBR Green-based real-time PCR of 752 miRNAs in 5 col6a1+/+(WT) and 6 col6a1-/- has been performed. Fifty one (6.5%) of the 333 miRNAs expressed in col6a1-/- mice serum, showed a significant dysregulation between col6a1-/- and WT mice serum. The statistical analysis revealed 17/51 miRNAs up-regulated and 34/51 down-regulated. To further characterized the dysregulated miRNAs we checked their involvement in disease related pathways coupled with literature analysis. These analyses showed that mmu-miR-195a-5p, mmu-miR-26a-5p, mmu-let-7c-5p and mmu-let-7b-5p are up-regulated in col6a1-/- mice serum, whereas mmu-miR-29b-3p and mmu-miR-29a-3p are downregulated ofd of. These observations are quite interesting because these miRNAs could play an important role in the collagen VI-related myopathies linking genes involved in essential signalling pathway for skeletal muscle cells development, differentiation or coding for ECM proteins. In particular miRNAs targets interfere with ERBb, MAPK, PIK3/Akt, mTOR, ECM-receptors, actin cytoskeleton, focal adhesion and calcium signalling. In conclusion, this project has identified 6 dysregulated microRNAs (mmu-miR-195a-5p, mmu-miR-26a-5p, mmu-let-7c-5p, mmu-let-7b-5p, mmu-miR-29b-3p and mmu-miR-29a-3p) that could be used in future studies as biomarkers and possibly as a tool for the diagnosis and the follow-up of collagen VI-related myopathies. Further analyses in larger cohorts of BM and UCMD patients are needed in order to validate the data obtained in mice models.