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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy
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Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy

机译：运动可以逆转淀粉样蛋白低聚物并延长基于αB-晶状蛋白的结蛋白相关性心肌病的存活

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摘要

The R120G mutation in the small heat shock-like protein αB-crystallin (CryAB~(R120G)) causes desmin-related myopathy (DRM), which is characterized by the formation of desmin- and CryAB-containing aggregates within muscle fibers. Mice with cardiac- specific overexpression of CryAB~(R120G) develop cardiomyopathy at 3 months and die at 6-7 months from heart failure (HF). Previous studies showed that overexpression of CryAB~(R120G) results in accumulation of preamyloid oligomer (PAO). PAO is considered to be the cytotoxic entity in many of the protein misfolding-based neurodegenerative diseases. On the basis of data from mouse models of neurodegenerative diseases showing that exercise or environmental enrichment reduces the amyloid oligomer level and improves cognitive ability, we hypothesized that CryAB~(R120G)-induced DRM would also respond favorably to prolonged voluntary exercise, reducing HF symptoms and rescuing the mice from premature death. Six months of voluntary exercise in CryAB~(R120G) animals resulted in 100% survival at a time when all unexercised mice had died. After 22 weeks of exercise, PAO levels were decreased by 47% compared with the unexercised CryAB~(R120G) control mice (P = 0.00001). Although CryAB~(R120G) expression led to decreased levels of the metallomembrane endopeptidase neprilysin, normal levels were maintained in the exercised CryAB~(R120G) mice, and in vitro loss-of-function and gain-of-function experiments using adenovirus-infected cardiomyocytes confirmed the importance of neprilysin in ameliorating PAO accumulation. The data demonstrate that voluntary exercise slows the progression to HF in the CryAB~(R120G) DRM model and that PAO accumulation is mediated, at least in part, by decreased neprilysin activity.
机译：小型热激样蛋白αB-晶状蛋白（CryAB〜（R120G））中的R120G突变会引起结蛋白相关性肌病（DRM），其特征是在肌肉纤维内形成含结蛋白和CryAB的聚集体。心脏特异性CryAB〜（R120G）过表达的小鼠在3个月时出现心肌病，在心力衰竭（HF）后6-7个月死亡。先前的研究表明，CryAB〜（R120G）的过表达导致淀粉样前低聚物（PAO）的积累。在许多基于蛋白质错误折叠的神经退行性疾病中，PAO被认为是细胞毒性实体。根据神经退行性疾病小鼠模型的数据显示，运动或环境富集可降低淀粉样蛋白低聚物水平并提高认知能力，我们假设CryAB〜（R120G）诱导的DRM对长时间的自愿运动也具有良好的反应，减少了HF症状并挽救小鼠免于过早死亡。当所有未经锻炼的小鼠死亡时，在CryAB〜（R120G）动物中进行六个月的自愿运动可导致100％的存活率。运动22周后，与未运动的CryAB〜（R120G）对照小鼠相比，PAO水平降低了47％（P = 0.00001）。尽管CryAB〜（R120G）的表达导致金属膜内肽酶中性溶酶水平降低，但在运动的CryAB〜（R120G）小鼠中以及在使用腺病毒感染的体外功能丧失和功能获得实验中，维持正常水平心肌细胞证实了neprilysin在改善PAO积累中的重要性。数据表明，在CryAB〜（R120G）DRM模型中，自愿运动减慢了向HF的进展，PAO的积累至少部分地由中性溶酶的活性介导。

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