RT info:eu-repo/semantics/article
T1 The Mitochondrial Na+/Ca2+ Exchanger Inhibitor CGP37157 Preserves Muscle Structure and Function to Increase Lifespan and Healthspan in Caenorhabditis elegans
A1 García-Casas, Paloma
A1 Alvarez-Illera, Pilar
A1 Gómez-Orte, Eva
A1 Cabello, Juan
A1 Fonteriz, Rosalba I.
A1 Montero Zoccola, María Teresa
A1 Álvarez Martín, Javier
K1 C. elegans, CGP37157, lifespan, endoplasmic reticulum, mitochondria, sarcopenia
AB We have reported recently that the mitochondrial Na+/Ca2+ exchanger inhibitor CGP37157 extends lifespan in Caenorhabditis elegans 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 C. elegans 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 aak-1;aak-2/AMP-activated kinase, sir-2.1/sirtuin, rsks-1/S6 kinase and daf-16/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 Ca2+ signalling and our results suggest that CGP37157 is probably inhibiting not only the mitochondrial Na+/Ca2+ exchanger, but also Ca2+ 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 ncx-6, one of the C. elegans mitochondrial Na+/Ca2+ exchangers. In summary, CGP37157 increases both lifespan and healthspan by a mechanism involving changes in cytosolic and mitochondrial Ca2+ homeostasis. Thus, Ca2+ signalling could bea promising target to act on aging.
PB Frontiers
SN 1663-9812
YR 2021
FD 2021
LK https://uvadoc.uva.es/handle/10324/66082
UL https://uvadoc.uva.es/handle/10324/66082
LA eng
NO Frontiers in Pharmacology, Junio 2021, 12, 695687
NO Producción Científica
DS UVaDOC
RD 09-nov-2024