Updated project metadata. It has been recently shown that RyR1 protein decrease induces in vivo most features of myopathy. However, the mechanisms underlying these disorders are not clarified. In the present study, using bioinformatics, OMICS, molecular biology and imaging system, we decipher how decreased RyR1 content in muscle cell leads to the development of muscle disease. Our results show that RyR1 depletion induces mitochondrial aggregation and dysfunction by defects in mitophagy and endoplasmic reticulum (ER)-mitochondrial tethering and alters lipid homeostasis. Those alterations are associated with the ER stress.