Intramuscular injection of Botox causes tendon atrophy by induction of senescence of tendon-derived stem cells.
Intramuscular injection of Botox causes tendon atrophy by induction of senescence of tendon-derived stem cells.
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肌肉注射肉毒杆菌可诱导肌腱干细胞衰老，导致肌腱萎缩
DOI：
10.1186/s13287-020-02084-w
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发表时间：
2021-01-07
影响因子：
7.5
通讯作者：
Zheng M
中科院分区：
文献类型：
--
作者：
Chen P;Chen Z;Mitchell C;Gao J;Chen L;Wang A;Leys T;Landao-Bassonga E;Zheng Q;Wang T;Zheng M
肉毒杆菌毒素(Botox)注射在临床上被广泛用于治疗肌肉痉挛和肌腱病变，但其作用机制尚不清楚。假设肌肉注射Botox后减少了髌腱的机械负荷，导致肌腱萎缩，这至少部分是通过诱导肌腱来源的干细胞(TDSCs)衰老来实现的。研究设计对照实验室研究方法将36只小鼠随机分为2组(注射肉毒杆菌毒素组和对照组各18只)。将肉毒杆菌注射到小鼠股四头肌的右侧股四头肌外侧(诱导机械应力剥夺膝腱)，或注射生理盐水作为对照。在注射后2 周，动物在获取组织以评估肌腱形态或进行体外研究之前被安乐死。在确定存活率、分化能力或衰老标志物的存在之前，通过细胞分选来分离TDSC，并评估它们对生物反应器中机械负荷的反应。结果注射肉毒杆菌素后2周，两组TDSCs均出现组织体积缩小、胶原纤维错位和降解增加等萎缩特征。集落形成实验显示，与对照组相比，注射肉毒杆菌组的TDSCs的集落形成单位数显著减少。注射肉毒杆菌后，TDSCs的多向分化能力也降低。为了检验机械剥夺的tDSC是否能够形成肌腱组织，我们使用隔离的生物反应器系统来培养使用tDSC的肌腱构造。这些结果表明，肉毒杆菌素处理组的TDSCs在适当的机械加载后未能恢复肌腱分化。信号通路检测显示，肌肉注射肉毒杆菌毒素可引起PTEN/AKT介导的TDSC细胞衰老。结论肌肉注射肉毒杆菌毒素通过诱导TDSCs的肌腱萎缩和衰老，干扰了肌腱的稳态。肉毒杆菌注射可能对肌腱病的治疗有长期的不良后果。临床相关性肌腱病或肌腱损伤的肌肉注射肉毒杆菌毒素可能会导致人体肌腱的不良反应，因此有必要对其长期疗效进行评估。
BackgroundBotulinum toxin (Botox) injection is in widespread clinical use for the treatment of muscle spasms and tendinopathy but the mechanism of action is poorly understood.HypothesisWe hypothesised that the reduction of patellar-tendon mechanical-loading following intra-muscular injection of Botox results in tendon atrophy that is at least in part mediated by the induction of senescence of tendon-derived stem cells (TDSCs).Study designControlled laboratory studyMethodsA total of 36 mice were randomly divided into 2 groups (18 Botox-injected and 18 vehicle-only control). Mice were injected into the rightvastus lateralisof quadriceps muscles either with Botox (to induce mechanical stress deprivation of the patellar tendon) or with normal saline as a control. At 2 weeks post-injection, animals were euthanized prior to tissues being harvested for either evaluation of tendon morphology or in vitro studies. TDSCs were isolated by cell-sorting prior to determination of viability, differentiation capacity or the presence of senescence markers, as well as assessing their response to mechanical loading in a bioreactor. Finally, to examine the mechanism of tendon atrophy in vitro, the PTEN/AKT-mediated cell senescence pathway was evaluated in TDSCs from both groups.ResultsTwo weeks after Botox injection, patellar tendons displayed several atrophic features including tissue volume reduction, collagen fibre misalignment and increased degradation. A colony formation assay revealed a significantly reduced number of colony forming units of TDSCs in the Botox-injected group compared to controls. Multipotent differentiation capacities of TDSCs were also diminished after Botox injection. To examine if mechanically deprived TDSC are capable of forming tendon tissue, we used an isolated bioreactor system to culture tendon constructs using TDSC. These results showed that TDSCs from the Botox-treated group failed to restore tenogenic differentiation after appropriate mechanical loading. Examination of the signalling pathway revealed that injection of Botox into quadriceps muscles causes PTEN/AKT-mediated cell senescence of TDSCs.ConclusionIntramuscular injection of Botox interferes with tendon homeostasis by inducing tendon atrophy and senescence of TDSCs. Botox injection may have long-term adverse consequences for the treatment of tendinopathy.Clinical relevanceIntramuscular Botox injection for tendinopathy or tendon injury could result in adverse effects in human tendons and evaluation of its long-term efficacy is warranted.
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影响因子：
7.8
作者：
Kohler J;Popov C;Klotz B;Alberton P;Prall WC;Haasters F;Müller-Deubert S;Ebert R;Klein-Hitpass L;Jakob F;Schieker M;Docheva D
通讯作者：
Docheva D
影响因子：
3
作者：
NAKAGAWA, Y;TOTSUKA, M;HIROTA, K
通讯作者：
HIROTA, K
影响因子：
17.1
作者：
Hwang J;Huang Y;Burwell TJ;Peterson NC;Connor J;Weiss SJ;Yu SM;Li Y
通讯作者：
Li Y
DOI：
10.3109/17453678208992224
发表时间：
1982-01-01
期刊：
ACTA ORTHOPAEDICA SCANDINAVICA
影响因子：
--
作者：
AMIEL, D;WOO, SLY;AKESON, WH
通讯作者：
AKESON, WH
影响因子：
3.7
作者：
Guo, Jia;Chan, Kai-Ming;Li, Gang
通讯作者：
Li, Gang