Exosomal Signaling by Skeletal Muscle: Role in Neuromuscular Ageing
Exosomal Signaling by Skeletal Muscle: Role in Neuromuscular Ageing
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骨骼肌的外泌体信号传导：在神经肌肉衰老中的作用
DOI：
10.1016/j.freeradbiomed.2020.10.268
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发表时间：
2020
影响因子：
7.4
通讯作者：
Hemmings K
中科院分区：
文献类型：
--
作者：
Hemmings K
哺乳动物的肌肉质量和功能随着年龄的增长而减少，这与神经肌肉相互作用的破坏有关。骨骼肌通过增加热休克蛋白（HSP）的表达对收缩产生强烈的应激反应，热休克蛋白促进肌肉重塑，促进蛋白质折叠和清除受损蛋白质。相比之下，其他类型的细胞，包括神经元细胞，不能产生应激反应。已经提出，热休克蛋白可以在外来体中从一种细胞类型转移到另一种细胞类型以维持受体细胞中的蛋白质稳态。因此，推测肌肉的强HSP应答通过HSP的外泌体转移为外周神经元细胞提供支持是诱人的。然而，在老年小鼠和人类中，肌肉收缩后产生的HSP减弱。我们假设老年小鼠肌肉不能产生HSP以响应收缩，导致外泌体HSP转移改变，因此不能维持运动神经元中的蛋白稳态，导致神经元和肌肉变性（1）。（6-8个月）和老年（24-26个月）小鼠，并使用非损伤性电刺激方案开始收缩（2）。从静止纤维和收缩后立即的纤维收集培养基，并使用总外泌体分离试剂盒（Thermo）纯化细胞外囊泡（EV）。使用NanoSight分析来确定EV的大小和数量。结果表明，成年小鼠和老年小鼠肌纤维收缩后释放的EVs总数无显著差异，但成年小鼠（2.7倍）和老年小鼠（3.1倍）肌纤维收缩后即刻释放的EVs增加幅度相似（沿着）。与此相反，与来自成年纤维的EV相比，来自老年小鼠纤维的EV的尺寸分布发生了改变，并且与静止的成年纤维的EV相比，由静止的老年纤维释放的EV的总蛋白含量显着减少（减少40%）。刺激后，老年小鼠EV的蛋白质含量低于成年小鼠，而成年小鼠EV的HSP 25和HSP 60的含量分别增加了2.5倍和2.5倍。相比之下，初步数据表明，老年小鼠静止肌纤维产生的电动汽车中的HSP 60含量已经升高，在收缩后几乎没有进一步增加，与体内肌肉的方式类似（3）。更多的数据将检查神经元细胞对EV的吸收以及供体年龄对其吸收能力的影响。支持或资助信息感谢国家老龄化研究所（AG 051442）和利物浦大学的慷慨支持。和 杰克逊，MJ。（2017年）。 等人（2008），Antioxid Redox Signal. 10：1463- 743Vasilaki，A.等（2006）。 机械老化发展127（11）：830- 9
Muscle mass and function are reduced with age in mammals and this is associated with disrupted neuromuscular interactions. Skeletal muscle mounts a robust stress response to contractions by an increased expression of Heat Shock Proteins (HSPs) that facilitate muscle remodeling, promote protein folding and clearance of damaged proteins. In contrast, other cell types including neuronal cells, are unable to mount a stress response. It has been proposed that HSPs may be transferred from one cell type to another in exosomes to maintain proteostasis in the recipient cells. Thus, speculation that the robust HSP response by muscle provides support to peripheral neuronal cells via exosomal transfer of HSPs is tempting. However, HSP generation by muscle following contractions is attenuated in old mice and humans. We hypothesise that inability of muscles of old mice to produce HSPs in response to contraction results in altered exosomal HSP transfer, and therefore a failure to maintain proteostasis in motor neurons, resulting in neuronal and muscle degeneration (1).Muscle fibres were isolated from flexor digitorum bravis (FDB) muscles of adult (6–8 month) and old (24–26 month) mice, and initiated to contract using a non‐damaging electrical stimulation protocol (2). Media was collected from quiescent fibres, and fibres immediately following contraction, and Extracellular Vesicles (EVs) purified using a Total Exosome Isolation kit (Thermo). NanoSight analysis was used to characterise the size and number of the EVs. Total protein content was determined and HSP levels were analysed by western blotting.Data demonstrated no significant difference in the total number of EVs released from quiescent fibres from adult and old mice, along with a similar increase in EVs released by muscle fibres of adult (2.7 fold) and old mice (3.1 fold) immediately following contraction compared with quiescent fibres. In contrast, the size distribution of the EVs from fibres of old mice was altered compared with EVs from adult fibres, and the total protein content of EVs was significantly less (40% decrease) in those released by quiescent old fibres compared with EVs of quiescent adult fibres. The lower protein content for EVs from old compared with adult fibres was maintained following stimulation.A 2.5 fold increase in HSP25 and a substantial increase in HSP60 content (from undetectable levels) was seen in EVs from fibres of adult mice immediately following contraction. In contrast, preliminary data suggested that the HSP60 content of EVs produced by quiescent muscle fibres from old mice is already elevated, with little further increase following contraction in a similar manner to muscles in vivo (3). Additional data will examine the uptake of EVs by neuronal cells and the effect of age of donor on their uptake ability.Support or Funding InformationWith thanks to National Institute of Ageing (AG051442) and the University of Liverpool for their generous support.1McArdle, A. and Jackson, MJ. ( 2017). Essays Biochem 61, 339– 348.2Palomero, J. et al ( 2008), Antioxid Redox Signal. 10: 1463– 743Vasilaki, A. et al ( 2006). Mech Ageing Dev. 127( 11): 830– 9
影响因子：
6.4
作者：
A. Mcardle;M. Jackson
通讯作者：
A. Mcardle;M. Jackson