Calcium Dyshomeostasis in β-Amyloid and Tau-bearing Skeletal Myotubes

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 beta-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(2)C(12)) expressed beta-amyloid-42 (Abeta(42)) and fetal Tau peptides, as human transgenes encoded by herpes simplex virus, either individually or concurrently. Co-expression of Abeta(42) in C(2)C(12) myotubes resulted in hyperphosphorylation of Tau protein that was not observed when Tau was expressed alone. Resting calcium concentration and agonist-induced RyR-mediated Ca(2+) release were examined using calcium-specific microelectrodes and Fluo-4 epifluorescence, respectively. Co-expression of Abeta(42) 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 Abeta(42) or Tau. In contrast, expression of Abeta(42), Tau, or Abeta(42) together with Tau resulted in enhanced sensitivity of ryanodine receptors to activation by caffeine. Notably, expression of beta-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 Ca(2+) leak and Tau hyperphosphorylation in skeletal muscle.