Autophagy and Mistargeting of Therapeutic Enzyme in Skeletal Muscle in Pompe Disease

Tokiko Fukuda, Meghan Ahearn, Ashley Roberts, Robert J. Mattaliano, Kristien Zaal, Evelyn Ralston, Paul H. Plotz, Nina Raben

Research output: Contribution to journalArticlepeer-review

140 Scopus citations


Enzyme replacement therapy (ERT) became a reality for patients with Pompe disease, a fatal cardiomyopathy and skeletal muscle myopathy caused by a deficiency of glycogen-degrading lysosomal enzyme acid α-glucosidase (GAA). The therapy, which relies on receptor-mediated endocytosis of recombinant human GAA (rhGAA), appears to be effective in cardiac muscle, but less so in skeletal muscle. We have previously shown a profound disturbance of the lysosomal degradative pathway (autophagy) in therapy-resistant muscle of GAA knockout mice (KO). Our findings here demonstrate a progressive age-dependent autophagic buildup in addition to enlargement of glycogen-filled lysosomes in multiple muscle groups in the KO. Trafficking and processing of the therapeutic enzyme along the endocytic pathway appear to be affected by the autophagy. Confocal microscopy of live single muscle fibers exposed to fluorescently labeled rhGAA indicates that a significant portion of the endocytosed enzyme in the KO was trapped as a partially processed form in the autophagic areas instead of reaching its target-the lysosomes. A fluid-phase endocytic marker was similarly mistargeted and accumulated in vesicular structures within the autophagic areas. These findings may explain why ERT often falls short of reversing the disease process and point toward new avenues for the development of pharmacological intervention.

Original languageEnglish (US)
Pages (from-to)831-839
Number of pages9
JournalMolecular Therapy
Issue number6
StatePublished - Dec 2006
Externally publishedYes


  • acid α-glucosidase
  • autophagy
  • endocytosis
  • enzyme replacement therapy
  • glycogen storage
  • lipofuscin
  • live cultured myofibers
  • lysosome

ASJC Scopus subject areas

  • Molecular Biology


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