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线粒体钠/钙交换体抑制剂CGP37157可维持肌肉结构和功能，从而延长线虫的寿命并提升其健康寿命。

The Mitochondrial Na/Ca Exchanger Inhibitor CGP37157 Preserves Muscle Structure and Function to Increase Lifespan and Healthspan in .

作者信息

García-Casas Paloma, Alvarez-Illera Pilar, Gómez-Orte Eva, Cabello Juan, Fonteriz Rosalba I, Montero Mayte, Alvarez Javier

机构信息

Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and CSIC, Valladolid, Spain.

Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain.

出版信息

Front Pharmacol. 2021 Jun 15;12:695687. doi: 10.3389/fphar.2021.695687. eCollection 2021.

DOI:10.3389/fphar.2021.695687
PMID:34211399
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8241105/
Abstract

We have reported recently that the mitochondrial Na/Ca exchanger inhibitor CGP37157 extends lifespan in by a mechanism involving mitochondria, the TOR pathway and the insulin/IGF1 pathway. Here we show that CGP37157 significantly improved the evolution with age of the sarcomeric regular structure, delaying development of sarcopenia in body wall muscle and increasing the average and maximum speed of the worms. Similarly, CGP37157 favored the maintenance of a regular mitochondrial structure during aging. We have also investigated further the mechanism of the effect of CGP37157 by studying its effect in mutants of /AMP-activated kinase, /sirtuin, /S6 kinase and /FOXO. We found that this compound was still effective increasing lifespan in all these mutants, indicating that these pathways are not involved in the effect. We have then monitored pharynx cytosolic and mitochondrial Ca signalling and our results suggest that CGP37157 is probably inhibiting not only the mitochondrial Na/Ca exchanger, but also Ca entry through the plasma membrane. Finally, a transcriptomic study detected that CGP37157 induced changes in lipid metabolism enzymes and a four-fold increase in the expression of 6, one of the mitochondrial Na/Ca exchangers. In summary, CGP37157 increases both lifespan and healthspan by a mechanism involving changes in cytosolic and mitochondrial Ca homeostasis. Thus, Ca signalling could be a promising target to act on aging.

摘要

我们最近报道，线粒体钠/钙交换抑制剂CGP37157通过一种涉及线粒体、TOR途径和胰岛素/IGF1途径的机制延长了线虫的寿命。在此，我们表明CGP37157显著改善了肌节规则结构随年龄的演变，延缓了线虫体壁肌肉中肌肉减少症的发展，并提高了线虫的平均速度和最大速度。同样，CGP37157有利于在衰老过程中维持规则的线粒体结构。我们还通过研究其在AMP激活激酶、sirtuin、S6激酶和FOXO突变体中的作用，进一步探究了CGP37157的作用机制。我们发现该化合物在所有这些突变体中仍能有效延长寿命，表明这些途径不参与其作用。然后，我们监测了咽部细胞质和线粒体的钙信号，结果表明CGP37157可能不仅抑制线粒体钠/钙交换体，还抑制通过质膜的钙内流。最后，一项转录组学研究检测到CGP37157诱导了脂质代谢酶的变化，并使线粒体钠/钙交换体之一的NCLX的表达增加了四倍。总之，CGP37157通过一种涉及细胞质和线粒体钙稳态变化的机制增加了寿命和健康寿命。因此，钙信号可能是作用于衰老的一个有前景的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/8aea7afe69bb/fphar-12-695687-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/6aaf4e7862de/fphar-12-695687-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/0bb5b615fffe/fphar-12-695687-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/cb38d2ed57ed/fphar-12-695687-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/4215374cb906/fphar-12-695687-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/e89e15a7b55c/fphar-12-695687-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/0648387c8b99/fphar-12-695687-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/8aea7afe69bb/fphar-12-695687-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/6aaf4e7862de/fphar-12-695687-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/0bb5b615fffe/fphar-12-695687-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/c0a0416f6dea/fphar-12-695687-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/0b03fb688703/fphar-12-695687-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/cb38d2ed57ed/fphar-12-695687-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/4215374cb906/fphar-12-695687-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/e89e15a7b55c/fphar-12-695687-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/0648387c8b99/fphar-12-695687-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56a3/8241105/8aea7afe69bb/fphar-12-695687-g009.jpg

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