Muscle precursor cells isolated from aged rats exhibit an increased tumor necrosis factor- alpha response.
Muscle precursor cells isolated from aged rats exhibit an increased tumor necrosis factor- alpha response.
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DOI：
10.1111/j.1474-9726.2008.00445.x
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发表时间：
2009-02
期刊：
影响因子：
7.8
通讯作者：
Booth FW
中科院分区：
文献类型：
--
作者：
Lees SJ;Zwetsloot KA;Booth FW
在衰老过程中，改善肌肉前体细胞（MPC，肌肉特异性干细胞）的功能被认为是改善与年龄相关的骨骼肌损失的关键治疗靶点。衰老过程中MPC功能障碍的发生与MPC人群的老化和骨骼肌环境的变化有关。先前的报道已经确定了衰老过程中循环和局部骨骼肌中TNF-α水平升高。本研究的目的是确定TNF-α-诱导的NF-κB活化和凋亡基因靶点的表达是否存在年龄相关的差异。与从3个月大的动物（3个月）分离的MPCs相比，从32个月大的动物（32个月）分离的MPCs在1、5和20 ng/ml TNF-α的作用下表现出更高的NF-κB活化。在TNF-α刺激2小时后，导致NF-κB激活的快速典型信号事件或TNF受体1、TNF受体2、TNF受体相关因子2 （TRAF2）或Fas (CD95) mRNA水平的升高没有观察到年龄差异。有趣的是，与3个月相比，32个月分离的MPCs中，TRAF2和细胞死亡诱导受体Fas （CD95）的mRNA水平在24小时TNF-α治疗后持续上调。我们的数据表明，年龄相关的NF-κB失活的调节机制可能存在差异，这可能对TNF-α-诱导的凋亡信号传导有影响。这些发现提高了我们对老年MPC与年龄相关环境变化之间相互作用的理解，这对于开发旨在改善MPC随年龄变化功能的潜在临床干预措施至关重要。
Improving muscle precursor cell (MPC, muscle-specific stem cells) function during aging has been implicated as a key therapeutic target for improving age-related skeletal muscle loss. MPC dysfunction during aging can be attributed to both the aging MPC population and the changing environment in skeletal muscle. Previous reports have identified elevated levels TNF-α in aging, both circulating and locally in skeletal muscle. The purpose of the present study was to determine if age-related differences existed between TNF-α-induced NF-κB activation and expression of apoptotic gene targets. MPCs isolated from 32-mo-old animals (32-mo) exhibited an increased NF-κB activation in response to 1, 5, and 20 ng/ml TNF-α, compared to MPCs isolated from 3-mo-old animals (3-mo). No age differences were observed in the rapid canonical signaling events leading to NF-κB activation or in the increase in mRNA levels for TNF receptor 1, TNF receptor 2, TNF receptor-associated factor 2 (TRAF2), or Fas (CD95) observed after 2 hr of TNF-α stimulation. Interestingly, mRNA levels for TRAF2 and the cell death inducing receptor, Fas (CD95) were persistently upregulated in response to 24 hr TNF-α treatment in MPCs isolated from 32-mo, compared to 3-mo. Our data indicate that age-related differences may exist in the regulatory mechanisms responsible for NF-κB inactivation, which may have an effect on TNF-α-induced apoptotic signaling. These findings improve our understanding of the interaction between aged MPCs and the changing environment associated with age, which is critical for the development of potential clinical interventions aimed at improving MPC function with age.