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J. Biol. Chem., Vol. 279, Issue 51, 53524-53532, December 17, 2004

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Calcium Dyshomeostasis in -Amyloid and Tau-bearing Skeletal Myotubes^*

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

From the Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135 and the ^¶Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

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 -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 (C₂C₁₂) expressed -amyloid-42 (A₄₂) and fetal Tau peptides, as human transgenes encoded by herpes simplex virus, either individually or concurrently. Co-expression of A₄₂ 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 A₄₂ 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 A₄₂ or Tau. In contrast, expression of A₄₂, Tau, or A₄₂ together with Tau resulted in enhanced sensitivity of ryanodine receptors to activation by caffeine. Notably, expression of -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.

Received for publication, July 27, 2004 , and in revised form, September 21, 2004.

^* This work was supported by National Institutes of Health Grant 1F32AR049160-1 (to A. S.), a grant from The Myositis Association, and NINDS National Institutes of Health Grants R01 NSO41373(to H. W. Q.) and 5R01ARO46513 (to P. D. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Caritas St. Elizabeth's Medical Center, Tufts University, 736 Cambridge St. Boston, MA 02135. Tel.: 617-789-2375; Fax: 617-789-5177; E-mail: henry.querfurth{at}tufts.edu.

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