More than a half of human core myopathies (CM) are caused by pathogenic RYR1 variants. SKM fibers of CM patients present mitochondrial defects and structural damages, resulting in variable clinical severity ranging from mild proximal muscle weakness to severe disability. Currently, there is no cure for RYR1-related myopathies.

RYR1Y524S/+ and RYR1I4895T/+ knock-in mice, respectively corresponding and equivalent to human RYR1—related core myopathies causing variants Y522S and I4898T, are widely recognized as compelling CM mouse models.

MiR-486 is a SKM enriched microRNA that participates in the fine-tuned regulation of muscle physiology. The central hypothesis of this proposal is that the skeletal muscle specific overexpression of miR-486 will have beneficial effects on mitochondrial activity and muscle function, will improve metabolism and trophism of RYR1Y524S/+ and RYR1I4895T/+ muscle fibers, finally resulting in relief of muscle defects. We will verify this hypothesis using two novel preclinical compound mouse models in which miR-486 is selectively overexpressed in skeletal muscle of knock-in heterozygous mice carrying either Y524S or I4895T RYR1 variants.

The project aims to evaluate the beneficial effects of miR-486 overexpression in overcoming the detrimental effects of RYR1 pathological variants on overall muscle functions and integrity, by performing morphological, biochemical, and functional-metabolic characterization of the SKM of these compound mice.