Calcium dyshomeostasis in β-amyloid and Tau-bearing skeletal myotubes
Calcium dyshomeostasis in β-amyloid and Tau-bearing skeletal myotubes
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DOI：
10.1074/jbc.m408473200
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发表时间：
2004-12-17
影响因子：
4.8
通讯作者：
Querfurth, HW
中科院分区：
文献类型：
--
作者：
Christensen, RA;Shtifman, A;Querfurth, HW
包涵体肌炎(IBM)中受包涵体影响的肌肉细胞或细胞死亡标志物的相对稀少与几种阿尔茨海默病(AD)相关蛋白的特异性和早期细胞内沉积是不同的。目前的研究检测了肌管β-淀粉样蛋白和/或Tau堆积与普遍存在的细胞内肌肉钙浓度处理不当之间的可能相关性，这可能是受影响患者持续虚弱的原因。培养的肌源性细胞(C2C12)单独或同时表达β-淀粉样蛋白42(Abeta(42))和胎儿Tau多肽，作为人类单纯疱疹病毒编码的转基因基因。在C2C12肌管中共表达Abeta(42)导致Tau蛋白过度磷酸化，这在单独表达Tau时没有观察到。用钙离子特异性微电极检测静息钙浓度，用Fluo-4荧光检测激动剂诱导的RyR介导的钙释放。Abeta(42)和Tau的共同表达协同提高了肌浆游离钙的基础水平，这一效应伴随着质膜的去极化。Abeta(42)或Tau不影响KCl去极化引起的肌浆网钙释放。相反，Abeta(42)、Tau或Abeta(42)与Tau一起表达导致Ryanodine受体对咖啡因激活的敏感性增强。值得注意的是，仅β-淀粉样蛋白的表达就足以导致对咖啡因直接激活的敏感性增加。目前的结果表明，淀粉样蛋白协同提高静息钙水平，这些作用与骨骼肌中被动的肌浆网钙离子泄漏和Tau过度磷酸化有关。
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 (C2C12) 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 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 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 Ca2+ leak and Tau hyperphosphorylation in skeletal muscle.