Lysosomal TRPML Channels in Myogenesis and Centronuclear Myopathies

X-linked Myotubular Myopathy (XLMTM) is a serious, life-threatening genetic disorder. It is caused by mutations in the Mtm1 gene that is needed for normal development and function of skeletal muscles. Affected individuals have difficulties with feeding and breathing due to muscle weakness. Because of their severe breathing problems, approximately fifty percent of individuals with XLMTM die before their first birthday, and few affected individuals reach adulthood. Currently, there are no treatments available for XLMTM. Autophagy is a self-recycling process that is essentially required for muscle development and maintenance. Muscle cells from XLMTM patients or mice display defective autophagy. Because loss of MTM1 causes accumulation of a lipid that activates TRPML1, a protein expressed in the cell recycling center-lysosome, and because our preliminary data have suggested that the activation of TRPML1 impairs autophagy, we aim to study the role of TRPML1 in XLMTM. Eventually, we hope to identify TRPML1 modulators that can correct muscle defects in XLMTM by facilitating autophagy. Our study will not only provide information regarding the role of TRPML1 in autophagy and muscle development, but also lead to new therapeutic strategies for XLMTM.