Enhanced glucose uptake in cardiac and skeletal muscles in Danon disease results from the impaired chaperone-mediated autophagy.

Danon disease (DD) is a rare X-linked lysosomal storage disorder that predominantly affects cardiac and skeletal muscles, characterized by glycogen and autophagic material accumulation. DD is caused by mutations in LAMP2, encoding a key mediator of lysosome-dependent autophagic degradation. A de novo nonsense mutation c.669 T > G (p. Tyr223Ter, LAMP2Y223*) was identified in a young DD patient. A knock-in mouse carrying the homologous mutation (Lamp2Y228*) successfully recapitulated the typical clinical features of DD, including a short PR interval and pre-excitation pattern. Transmission electron microscopy and immunofluorescence assays showed aberrant autophagolysosomes and glycogen accumulation in both cardiac and skeletal muscle tissues. Mechanistic studies in vivo and in vitro demonstrated the impaired chaperone-mediated autophagy (CMA) and increased glucose uptake through the CMA-dependent RAB10-GLUT4 pathway following mutant LAMP2 expression. These findings identify a RAB10-GLUT4 axis linking LAMP2 deficiency to the enhanced glucose uptake and further implicate this pathway as a contributor of glycogen accumulation in DD.