Muscle Wasting in Aged, Sarcopenic Rats Is Associated with Enhanced Activity of the Ubiquitin Proteasome Pathway
Muscle Wasting in Aged, Sarcopenic Rats Is Associated with Enhanced Activity of the Ubiquitin Proteasome Pathway
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DOI：
10.1074/jbc.m110.129718
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发表时间：
2010-12-17
影响因子：
4.8
通讯作者：
Ulfhake, Brun
中科院分区：
文献类型：
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作者：
Altun, Mikael;Besche, Henrike C.;Ulfhake, Brun
衰老生物体的标志之一是错误折叠蛋白质的积累和骨骼肌质量的减少（“肌肉减少症”）。我们研究了衰老和饮食限制（延缓许多与年龄相关的变化）对肌肉中泛素蛋白酶体系统（UPS）组分的影响。老年（30个月大）大鼠后肢肌肉显示出明显的肌肉质量损失，26 S蛋白酶体的水平比成年（4个月大）对照组高2-3倍。从老年大鼠和成年大鼠肌肉中纯化的26 S蛋白酶体显示出类似的降解肽、蛋白质和泛素化底物的能力，但蛋白酶体相关蛋白的水平不同（例如：G.泛素连接酶E6 AP和去泛素化酶USP 14）。此外，许多其他去泛素化酶的活性在老年肌肉中大大增强。然而，它们的多泛素化蛋白质含量高于成年动物。老化的肌肉含有更高水平的泛素连接酶CHIP，参与消除错误折叠的蛋白质，和MuRF 1，泛素化肌原纤维蛋白。这些肌肉与由于疾病、禁食或废用而快速萎缩的肌肉不同，Atrogin-1/MAFbx表达低，并且不能被糖皮质激素诱导。因此，老年大鼠的肌肉显示出许多适应性变化，表明UPS增强了蛋白质水解，这可能增强了它们消除错误折叠蛋白质的能力，似乎有助于肌肉减少症。因此，饮食限制减少或阻止了蛋白酶体和其他UPS组分的衰老相关增加，并减少了肌肉萎缩。
Among the hallmarks of aged organisms are an accumulation of misfolded proteins and a reduction in skeletal muscle mass ("sarcopenia"). We have examined the effects of aging and dietary restriction (which retards many age-related changes) on components of the ubiquitin proteasome system (UPS) in muscle. The hindlimb muscles of aged (30 months old) rats showed a marked loss of muscle mass and contained 2-3-fold higher levels of 26S proteasomes than those of adult (4 months old) controls. 26S proteasomes purified from muscles of aged and adult rats showed a similar capacity to degrade peptides, proteins, and an ubiquitylated substrate, but differed in levels of proteasome-associated proteins (e. g. the ubiquitin ligase E6AP and deubiquitylating enzyme USP14). Also, the activities of many other deubiquitylating enzymes were greatly enhanced in the aged muscles. Nevertheless, their content of polyubiquitylated proteins was higher than in adult animals. The aged muscles contained higher levels of the ubiquitin ligase CHIP, involved in eliminating misfolded proteins, and MuRF1, which ubiquitylates myofibrillar proteins. These muscles differed from ones rapidly atrophying due to disease, fasting, or disuse in that Atrogin-1/MAFbx expression was low and not inducible by glucocorticoids. Thus, the muscles of aged rats showed many adaptations indicating enhanced proteolysis by the UPS, which may enhance their capacity to eliminate misfolded proteins and seems to contribute to the sarcopenia. Accordingly, dietary restriction decreased or prevented the aging-associated increases in proteasomes and other UPS components and reduced muscle wasting.