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Peer-reviewedCC BY-NC-NDCell & bioscience

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

  • Wei Lai1,2
  • Dandan Zhang1,2
  • Rong Wan2,3
  • Yang Liu1,2
  • Yuhao Su2,3
  • Qinmei Xiong1
  • Qiongqiong Zhou1
  • Jinzhu Hu1
  • Xueliang Qi4
  • Jinyan Xie2,3
  • Xia Yan2,3
  • Qi Chen2,3
4 more authors
  • Yang Shen5,6
  • Juxiang Li7
  • Ali J Marian8
  • Kui Hong9,10,11
11 affiliations
  1. 1Department of Cardiovascular Medicine, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China.
  2. 2Jiangxi Key Laboratory of Molecular Medicine, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
  3. 3Department of Genetics Medicine, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
  4. 4Department of Neurology, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
  5. 5Jiangxi Key Laboratory of Molecular Medicine, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China. [email protected].
  6. 6Department of Genetics Medicine, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China. [email protected].
  7. 7Department of Cardiovascular Medicine, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China. [email protected].
  8. 8Center for Cardiovascular Genetics, Institute of Molecular Medicine, the University of Texas Health Science Center-Houston, Houston, TX, 77030, USA.
  9. 9Department of Cardiovascular Medicine, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China. [email protected].
  10. 10Jiangxi Key Laboratory of Molecular Medicine, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China. [email protected].
  11. 11Department of Genetics Medicine, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China. [email protected].
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{lai2026enhanced,
  title = {{Enhanced glucose uptake in cardiac and skeletal muscles in Danon disease results from the impaired chaperone-mediated autophagy.}},
  author = {Wei Lai and Dandan Zhang and Rong Wan and Yang Liu and Yuhao Su and Qinmei Xiong and Qiongqiong Zhou and Jinzhu Hu and Xueliang Qi and Jinyan Xie and Xia Yan and Qi Chen and Yang Shen and Juxiang Li and Ali J Marian and Kui Hong},
  journal = {Cell \& bioscience},
  year = {2026},
  month = jul,
  doi = {10.1186/s13578-026-01625-9},
  url = {https://europepmc.org/article/MED/42907875},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Enhanced glucose uptake in cardiac and skeletal muscles in Danon disease results from the impaired chaperone-mediated autophagy.
AU  - Wei Lai
AU  - Dandan Zhang
AU  - Rong Wan
AU  - Yang Liu
AU  - Yuhao Su
AU  - Qinmei Xiong
AU  - Qiongqiong Zhou
AU  - Jinzhu Hu
AU  - Xueliang Qi
AU  - Jinyan Xie
AU  - Xia Yan
AU  - Qi Chen
AU  - Yang Shen
AU  - Juxiang Li
AU  - Ali J Marian
AU  - Kui Hong
PY  - 2026
DA  - 2026/07/01
JO  - Cell & bioscience
DO  - 10.1186/s13578-026-01625-9
UR  - https://europepmc.org/article/MED/42907875
AB  - 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.
SN  - 2045-3701
ER  -