Carboxyl-terminal modulator protein (CTMP) deficiency mitigates denervation-induced skeletal muscle atrophy.
Carboxyl-terminal modulator protein (CTMP) deficiency mitigates denervation-induced skeletal muscle atrophy.
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DOI：
10.1016/j.bbrc.2023.01.023
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发表时间：
2023-01
影响因子：
3.1
通讯作者：
Junmei Wang;Lydia Tierney;Christopher Wilson;V. Phillips;Lillian Goldman;Christen L. Mumaw;En Muang-En
中科院分区：
文献类型：
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作者：
Junmei Wang;Lydia Tierney;Christopher Wilson;V. Phillips;Lillian Goldman;Christen L. Mumaw;En Muang-En
去神经骨骼肌显示Akt活性和磷酸化降低，导致萎缩。Akt抑制肌环指蛋白1 （MuRF-1）等萎缩相关泛素连接酶的下游转录。此外，Akt信号的减少会导致肌肉中蛋白质合成的异常。在ALS小鼠中，我们最近发现萎缩骨骼肌中羧基终止物调节蛋白（CTMP）表达增加，并与Akt信号传导减少相关。在肌萎缩模型中，CTMP也参与促进肌肉退化和分解代谢。本研究考察了坐骨神经损伤（SNI）是否刺激了失神经骨骼肌中CTMP的表达。我们假设CTMP缺乏会减少神经源性萎缩并逆转Akt信号下调。与未受影响的对侧肌肉相比，野生型（WT）腓肠肌CTMP显著升高（p < 0.05）。此外，去神经CTMP敲除（CTMP- ko）腓肠肌重量大于WT肌（p < 0.05）。去神经CTMP-KO腓肠肌Akt和下游糖原合成酶激酶3β (GSK3β)磷酸化水平也高于WT肌（p < 0.05），核糖体蛋白S6和4E-BP1磷酸化水平也高于WT肌（p < 0.001和p < 0.05）。此外，CTMP-KO小鼠的E3泛素连接酶MuRF-1和肌肉生长抑制素水平明显低于WT肌肉（p < 0.05）。我们的研究结果表明，CTMP对去神经支配后的肌肉萎缩至关重要，它可能通过减少Akt信号、蛋白质合成和增加心肌细胞分解代谢来起作用。
Denervated skeletal muscles show decreased Akt activity and phosphorylation, resulting in atrophy. Akt inhibits downstream transcription of atrophy-associated ubiquitin ligases like muscle ring-finger protein 1 (MuRF-1). In addition, reduced Akt signaling contributes to aberrant protein synthesis in muscles. In ALS mice, we recently found that carboxyl-terminator modulator protein (CTMP) expression is increased and correlated with reduced Akt signaling in atrophic skeletal muscle. CTMP has also been implicated in promoting muscle degeneration and catabolism in anin vitromuscle atrophy model. The present study examined whether sciatic nerve injury (SNI) stimulated CTMP expression in denervated skeletal muscle during muscle atrophy. We hypothesized that CTMP deficiency would reduce neurogenic atrophy and reverse Akt signaling downregulation. Compared to the unaffected contralateral muscle, wild-type (WT) gastrocnemius muscle had a significant increase in CTMP (p < 0.05). Furthermore, denervated CTMP knockout (CTMP-KO) gastrocnemius weighed more than WT muscle (p < 0.05). Denervated CTMP-KO gastrocnemius also showed higher Akt and downstream glycogen synthase kinase 3β (GSK3β) phosphorylation compared to WT muscle (p < 0.05) as well as ribosomal proteins S6 and 4E-BP1 phosphorylation (p < 0.001 and p < 0.05, respectively). Moreover, CTMP-KO mice showed significantly lower levels of E3 ubiquitin ligase MuRF-1 and myostatin than WT muscle (p < 0.05). Our findings suggest that CTMP is essential to muscle atrophy after denervation and it may act by reducing Akt signaling, protein synthesis, and increasing myocellular catabolism.