Lack of muscle recovery after immobilization in old rats does not result from a defect in normalization of the ubiquitin-proteasome and the caspase-dependent apoptotic pathways
Lack of muscle recovery after immobilization in old rats does not result from a defect in normalization of the ubiquitin-proteasome and the caspase-dependent apoptotic pathways
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DOI：
10.1113/jphysiol.2010.201707
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发表时间：
2011-02-01
影响因子：
5.5
通讯作者：
Combaret, Lydie
中科院分区：
文献类型：
--
作者：
Magne, Hugues;Savary-Auzeloux, Isabelle;Combaret, Lydie
非技术摘要由于活动能力下降和/或需要卧床休息的病理发作增加，固定时间随着年龄的增长而增加。那么，肌肉减少症的部分原因可能是由于肌肉蛋白质代谢、细胞凋亡和细胞再生的不平衡，在分解代谢状态后骨骼肌质量的恢复受损。肌肉恢复过程中涉及的机制很少被研究，而且对于老年人来说，这些机制几乎仍然未知。我们在大鼠身上发现，衰老过程中短暂的不动会引发肌肉萎缩，而这种萎缩在 40 天后确实没有恢复。固定化与泛素蛋白酶体和线粒体相关凋亡途径以及炎症和氧化还原过程的激活以及细胞再生的减少有关。我们发现，衰老过程中肌肉恢复的缺乏并不是由于蛋白水解或细胞凋亡下调的缺陷造成的。这些观察结果使我们推测，固定后的肌肉蛋白质合成激活在衰老过程中发生了变化。由于活动能力下降和/或需要卧床休息的病理发作增加，固定时间随着年龄的增长而增加。肌肉减少症的部分原因可能是由于肌肉蛋白质代谢、细胞凋亡和细胞再生的不平衡，在分解代谢状态后骨骼肌质量的恢复受损。肌肉恢复的机制尚未得到充分研究，并且在老年人中几乎仍然未知。本研究旨在研究衰老过程中固定和随后恢复过程中蛋白酶依赖性细胞凋亡和泛素蛋白酶体依赖性蛋白水解途径的调节。对老年大鼠（22-24月龄）进行单侧后肢铸造8天（I8），并允许恢复10至40天（R10至R40）。固定腓肠肌萎缩了21%，即使在R40也没有恢复。凋亡指数、多聚泛素化缀合物的量、蛋白酶体胰凝乳蛋白酶和胰蛋白酶样、凋亡体连接的 caspase-9、-3 和 -8 活性在 I8 时增加。相反，生肌因子 myf-5 的量在 I8 时下降。这些变化与肌内炎症和氧化应激的增加同时发生。所有这些参数在 R10 后均已归一化。固定肌肉中的 XIAP/Smac-DIABLO 蛋白比率下降了一半，并且在恢复过程中保持较低水平。令人惊讶的是，非固定腿也因 R20 而萎缩，同时 XIAP/Smac-DIABLO 蛋白比率降低。总而言之，这表明衰老过程中固定不动后的恢复受损并不是由于半胱天冬酶依赖性细胞凋亡和泛素蛋白酶体依赖性途径缺乏正常化所致，而且固定可能会导致全身肌肉损失，然后导致老年人肌肉减少症的发生。
Non-technical summaryImmobilization periods increase with age because of decreased mobility and/or because of increased pathological episodes that require bed-rest. Then, sarcopaenia might be partially explained by an impaired recovery of skeletal muscle mass after a catabolic state due to an imbalance of muscle protein metabolism, apoptosis and cellular regeneration. Mechanisms involved during muscle recovery have been little studied and in elderly they remain almost unknown. We show, in rats, that a short immobilization period during ageing initiated muscle atrophy that was indeed not recovered after 40 days. Immobilization was associated with an activation of both the ubiquitin-proteasome and the mitochondria-associated apoptotic pathways and the inflammatory and redox processes, and a decrease of cellular regeneration. We show that the lack of muscle recovery during ageing is not due to a defect in proteolysis or apoptosis down-regulation. These observations lead us to hypothesize that muscle protein synthesis activation after immobilization was altered during ageing.Immobilization periods increase with age because of decreased mobility and/or increased pathological episodes that require bed-rest. Sarcopaenia might be partially explained by an impaired recovery of skeletal muscle mass after a catabolic state due to an imbalance of muscle protein metabolism, apoptosis and cellular regeneration. Mechanisms involved in muscle recovery have been poorly investigated, and remain almost unknown in the elderly. This study aimed at studying the regulation of the capsase-dependent apoptotic and the ubiquitin-proteasome-dependent proteolytic pathways during immobilization and subsequent recovery during ageing. Old rats (22-24-months old) were subjected to unilateral hindlimb casting for 8 days (I8) and allowed to recover for 10 to 40 days (R10 to R40). Immobilized gastrocnemius muscles atrophied by 21%, and did not recover even at R40. Apoptotic index, amount of polyubiquitinated conjugates, proteasome chymotrypsin- and trypsin-like, apoptosome-linked caspase-9, -3, and -8 activities increased at I8. Conversely, the amount of the myogenic factor myf-5 decreased at I8. These changes paralleled the increase of intramuscular inflammation and oxidative stress. All these parameters normalized as soon as R10. The XIAP/Smac-DIABLO protein ratio decreased by half in immobilized muscles and remained low during recovery. Surprisingly, the non-immobilized leg also atrophied from R20, concomitantly with a decreased XIAP/Smac-DIABLO protein ratio. Altogether, this suggests that the impaired recovery following immobilization in ageing does not result from a lack of normalization of the caspase-dependent apoptotic and the ubiquitin-proteasome-dependent pathways, and also that immobilization could induce a general muscle loss and then contribute to the development of sarcopaenia in elderly.