Na+ Dysregulation Coupled with Ca2+ entry through NCX1 Promotes Muscular dystrophy in mice

Adam R. Burr, Douglas P. Millay, Sanjeewa A. Goonasekera, Ki Ho Park, Michelle A. Sargent, James Collins, Francisco Altamirano, Kenneth D. Philipson, Paul D. Allen, Jianjie Ma, José Rafael López, Jeffery D. Molkentina

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Unregulated Ca2+ entry is thought to underlie muscular dystrophy. Here, we generated skeletal-muscle-specific transgenic (TG) mice expressing the Na+-Ca2+ exchanger 1 (NCX1) to model its identified augmentation during muscular dystrophy. The NCX1 transgene induced dystrophy-like disease in all hind-limb musculature, as well as exacerbated the muscle disease phenotypes in δ-sarcoglycan (Sgcd-/-), Dysf-/-, and mdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of the Slc8a1 (NCX1) gene diminished hind-limb pathology in Sgcd-/- mice. Measured increases in baseline Na+ and Ca2+ in dystrophic muscle fibers of the hind-limb musculature predicts a net Ca2+ influx state due to reverse-mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm, where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward-mode NCX1 operation that reduces Ca2+ levels. Indeed, Atp1a2+/- (encoding Na+-K+ ATPase α2) mice, which have reduced Na+ clearance rates that would favor NCX1 reverse-mode operation, showed exacerbated disease in the hind limbs of NCX1 TG mice, similar to treatment with the Na+-K+ ATPase inhibitor digoxin. Treatment of Sgcd-/- mice with ranolazine, a broadly acting Na+ channel inhibitor that should increase NCX1 forward- mode operation, reduced muscular pathology.

Original languageEnglish (US)
Pages (from-to)1991-2002
Number of pages12
JournalMolecular and Cellular Biology
Volume34
Issue number11
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Burr, A. R., Millay, D. P., Goonasekera, S. A., Park, K. H., Sargent, M. A., Collins, J., Altamirano, F., Philipson, K. D., Allen, P. D., Ma, J., López, J. R., & Molkentina, J. D. (2014). Na+ Dysregulation Coupled with Ca2+ entry through NCX1 Promotes Muscular dystrophy in mice. Molecular and Cellular Biology, 34(11), 1991-2002. https://doi.org/10.1128/MCB.00339-14