Calcium dyshomeostasis in β-amyloid and tau-bearing skeletal myotubes

Rial A. Christensen, Alexander Shtifman, Paul D. Allen, Jose R. Lopez, Henry W. Querfurth

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

The relative scarcity of inclusion-affected muscle cells or markers of cell death in inclusion body myositis (IBM) is in distinction to the specific and early intracellular deposition of several Alzheimer's Disease (AD)-related proteins. The current study examined the possible correlation between myotube β-amyloid and/or Tau accumulations and a widespread mishandling of intracellular muscle calcium concentration that could potentially account for the unrelenting weakness in affected patients. Cultured myogenic cells (C 2C12) expressed β-amyloid-42 (Aβ42) and fetal Tau peptides, as human transgenes encoded by herpes simplex virus, either individually or concurrently. Co-expression of Aβ42 in C2C12 myotubes resulted in hyperphosphorylation of Tau protein that was not observed when Tau was expressed alone. Resting calcium concentration and agonist-induced RyR-mediated Ca2+ release were examined using calcium-specific microelectrodes and Fluo-4 epifluorescence, respectively. Co-expression of Aβ42 and Tau cooperatively elevated basal levels of myoplasmic-free calcium, an effect that was accompanied by depolarization of the plasma membrane. Sarcoplasmic reticulum (SR) calcium release, induced by KCl depolarization, was not affected by Aβ42 or Tau. In contrast, expression of Aβ42, Tau, or Aβ42 together with Tau resulted in enhanced sensitivity of ryanodine receptors to activation by caffeine. Notably, expression of β-amyloid, alone, was sufficient to result in an increased sensitivity to direct activation by caffeine. Current results indicate that amyloid proteins cooperate to raise resting calcium, levels and that these effects are associated with a passive SR Ca2+ leak and Tau hyperphosphorylation in skeletal muscle.

Original languageEnglish (US)
Pages (from-to)53524-53532
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number51
DOIs
StatePublished - Dec 17 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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    Christensen, R. A., Shtifman, A., Allen, P. D., Lopez, J. R., & Querfurth, H. W. (2004). Calcium dyshomeostasis in β-amyloid and tau-bearing skeletal myotubes. Journal of Biological Chemistry, 279(51), 53524-53532. https://doi.org/10.1074/jbc.M408473200