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Upregulation of voltage-gated calcium channels and oxidative stress in Pompe disease

Thursday, November 07, 2013 — Poster Session II

12:00 p.m. – 2:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • J.A. Lim
  • N. Raben


Pompe disease, a deficiency of glycogen-degrading lysosomal enzyme - acid alpha-glucosidase (GAA), is a severe cardiac and skeletal muscle myopathy. The currently available enzyme replacement therapy reverses cardiac but not skeletal muscle pathology. This is partly the result of poor understanding of the pathogenesis of muscle damage in Pompe disease. Our recent data identified autophagy dysfunction as a major component of muscle pathology in addition to lysosomal storage. However, other abnormalities likely play a role. In an effort to discover novel pathogenic mechanisms, we compared protein and mRNA expression levels in muscle from GAA-KO and WT mice. In the KO, we found a dramatic increase in the levels of isoforms of the L-type calcium channel. Consistent with these in vivo data, intracellular Ca2+ concentration and flux in Pompe myotubes was significantly increased compared to that in the WT. As expected, the raise in the intracellular Ca2+ in Pompe myotubes was associated with oxidative stress. Activation of L-type calcium channel, as well as mitochondrial ROS production due to disturbed autophagy, may be responsible for the excessive production of oxidants in Pompe muscle cells, suggesting that calcium channel blockers may have a beneficial effect in Pompe disease.

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