Age Related Changes in Muscle Mass and Force Generation in the Triple Transgenic (3xTgAD) Mouse Model of Alzheimer's Disease.
Age Related Changes in Muscle Mass and Force Generation in the Triple Transgenic (3xTgAD) Mouse Model of Alzheimer's Disease.
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DOI：
10.3389/fnagi.2022.876816
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
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新出现的证据表明，阿尔茨海默病（AD）患者可能表现出加速的肌肉减少症表型。为了研究与神经元死亡和认知功能障碍相关的病理变化是否也发生在外周运动神经元和肌肉中作为年龄的函数，我们使用AD的三重转基因小鼠模型（3xTgAD小鼠），其携带与AD病理相关的APP、Tau和早老素蛋白的突变形式的转基因。我们测量了年轻（2至4个月）雌性对照组和3xTgAD小鼠以及老年（18-20个月）对照组和3xTgAD雌性小鼠运动神经元和骨骼肌功能和代谢的变化。在年龄较大的3xTgAD小鼠中，我们观察到许多肌肉减少症相关的表型，包括显著碎片化和去神经支配的神经肌肉接头（NMJ），与坐骨神经诱导的收缩力产生相比，直接肌肉刺激诱导的收缩力产生减少17%，腓肠肌质量减少30%。相反，在年轻的3xTgAD小鼠中没有发现这些结果。我们还测量了老年3xTgAD小鼠骨骼肌和神经元组织中淀粉样蛋白-β（Aβ）的蓄积，这可能导致老年3xTgAD小鼠的肌肉萎缩和NMJ破坏。此外，TGF-β介导的萎缩信号通路在老年3xTgAD小鼠中被激活，并且是该组中发生的肌肉萎缩的潜在促成因素。也许令人惊讶的是，线粒体耗氧量和活性氧（ROS）的产生并没有在骨骼肌从老3xTgAD小鼠升高。总之，这些结果为AD病理机制对骨骼肌外周变化的影响提供了新的见解。
Emerging evidence suggests that patients with Alzheimer’s disease (AD) may show accelerated sarcopenia phenotypes. To investigate whether pathological changes associated with neuronal death and cognitive dysfunction also occur in peripheral motor neurons and muscle as a function of age, we used the triple transgenic mouse model of AD (3xTgAD mice) that carries transgenes for mutant forms of APP, Tau, and presenilin proteins that are associated with AD pathology. We measured changes in motor neurons and skeletal muscle function and metabolism in young (2 to 4 month) female control and 3xTgAD mice and in older (18–20 month) control and 3xTgAD female mice. In older 3xTgAD mice, we observed a number of sarcopenia-related phenotypes, including significantly fragmented and denervated neuromuscular junctions (NMJs) associated with a 17% reduction in sciatic nerve induced vs. direct muscle stimulation induced contractile force production, and a 30% decrease in gastrocnemius muscle mass. On the contrary, none of these outcomes were found in young 3xTgAD mice. We also measured an accumulation of amyloid-β (Aβ) in both skeletal muscle and neuronal tissue in old 3xTgAD mice that may potentially contribute to muscle atrophy and NMJ disruption in the older 3xTgAD mice. Furthermore, the TGF-β mediated atrophy signaling pathway is activated in old 3xTgAD mice and is a potential contributing factor in the muscle atrophy that occurs in this group. Perhaps surprisingly, mitochondrial oxygen consumption and reactive oxygen species (ROS) production are not elevated in skeletal muscle from old 3xTgAD mice. Together, these results provide new insights into the effect of AD pathological mechanisms on peripheral changes in skeletal muscle.
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影响因子：
7.8
作者：
Bhaskaran S;Pollock N;C Macpherson P;Ahn B;Piekarz KM;Staunton CA;Brown JL;Qaisar R;Vasilaki A;Richardson A;McArdle A;Jackson MJ;Brooks SV;Van Remmen H
通讯作者：
Van Remmen H
影响因子：
2.1
作者：
Monteiro-Cardoso, Vera F.;Castro, Marisa;Videira, Romeu A.
通讯作者：
Videira, Romeu A.
影响因子：
7.8
作者：
Belfiore, Ramona;Rodin, Alexis;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
影响因子：
6
作者：
Audouard, Emilie;Van Hees, Laura;Brion, Jean-Pierre
通讯作者：
Brion, Jean-Pierre
影响因子：
5.5
作者：
Murphy, Robyn M.;Xu, Hongyang;Stapleton, David I.
通讯作者：
Stapleton, David I.