cholecalciferol and Muscular-Dystrophies

Dysferlinopathies are a heterogenous group of autosomal recessive inherited muscular dystrophies caused by mutations in DYSF gene. Dysferlin is expressed mainly in skeletal muscle and in monocytes and patients display a severe reduction or absence of protein in both tissues. Vitamin D3 promotes differentiation of the promyelocytic leukemia HL60 cells. We analyzed the effect of vitamin D3 on dysferlin expression in vitro using HL60 cells, monocytes and myotubes from controls and carriers of a single mutation in DYSF. We also performed an observational study with oral vitamin D3 in a cohort of 21 carriers. Fifteen subjects were treated for 1 year and dysferlin expression in monocytes was analysed before and after treatment. Treatment with vitamin D3 increased expression of dysferlin in vitro. The effect of vitamin D3 was mediated by both a nongenomic pathway through MEK/ERK and a genomic pathway involving binding of vitamin D3 receptor to the dysferlin promoter. Carriers treated with vitamin D3 had significantly increased expression of dysferlin in monocytes compared with nontreated carriers (P < 0.05). These findings will have important therapeutic implications since a combination of different molecular strategies together with vitamin D3 uptake could increase dysferlin expression to nonpathological protein levels.

Topics: Adult; Aged; Aged, 80 and over; Cell Differentiation; Cholecalciferol; Dysferlin; Female; Follow-Up Studies; HEK293 Cells; Heterozygote; HL-60 Cells; Humans; Luciferases; Male; Membrane Proteins; Middle Aged; Monocytes; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophies; Mutation; Phosphorylation; Plasmids; Prospective Studies; Real-Time Polymerase Chain Reaction; Receptors, Calcitriol; Spain; Young Adult