MicroRNA signatures predict dysregulated Vitamin D receptor and calcium pathways status in Limb Girdle muscle dystrophies (LGMD) 2A/2B.

Limb-girdle muscular dystrophy 2A (LGMD2A) or calpainopathy, caused by absence or altered functions of the calcium-dependent cysteine protease calpain 3, is considered the most frequent form of recessive LGMD worldwide. A secondary reduction of calpain 3 can also be observed in dysferlinopathy or LGMD2B, a distinct type of LGMD caused by deficiency of functional dysferlin protein. The purpose of the present study was to identify by TaqMan Low Density Array technology the potential role of selected miRNAs in three groups of five patients each, characterized by primary, autocatalytic and secondary calpain 3 deficits. A total of 187 miRNAs were found dysregulated at a significant level in all patients compared with controls, with 6 miRNAs showing opposite regulation in LGMD2A vs LGMD2B patients. By search on Mirpath and Microcosm databases, part of the dysregulated miRNAs resulted participating in growth and differentiation processes as well as in muscle development, while the remaining primarly involved in inflammation and calcium metabolism. Finally, expression analysis of two genes predicted as controlled by calcium-assigned miRNAs, Vitamin D Receptor and Guanine Nucleotide Binding protein beta polypeptide 1, showed an evident upregulation in LGMD2B patients, in accordance with miRNA levels (miR-129 and miR-493). Taken together, our data support alterations in calcium pathway status as an important factor in the progressive functional decline of the dystrophic muscle fibers, suggesting myofiber calcium imbalance as a potential therapeutic target to slow down the disease progression and limit the degenerative process, more evident in LGMD2B.