The Mitochondrial Na+/Ca2+ Exchanger Inhibitor CGP37157 Preserves Muscle Structure and Function to Increase Lifespan and Healthspan in Caenorhabditis elegans

Abstract

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 be a promising target to act on aging.

The transforming growth factor beta ligand TIG-2 modulates the function of neuromuscular junction and muscle energy metabolism in Caenorhabditis elegans

“…Previous research revealed that mitochondrial Ca 2+ is essential for the regulation of mitochondrial function and ATP generation ( García-Casas et al, 2021 ). To check whether the decrease in ATP results from the decline in mitochondrial Ca 2+ , the mitochondrial Ca 2+ level in muscle cells was analyzed by monitoring the intensity of GCaMP, a genetic fluorescent mitochondrial calcium indicator.…”

SERCA inhibition improves lifespan and healthspan in a chemical model of Parkinson disease in Caenorhabditis elegans

“…In our laboratory we have recently found that modulation of some systems involved in intracellular Ca 2+ homeostasis is capable of extending lifespan and improving functional parameters representative of better health in C. elegans nematodes ( García-Casas et al, 2018 ; 2019 ; 2021a ; 2021b ). One of these systems is the ER Ca 2+ pump or SERCA, whose partial inhibition, either with inhibitors or with RNAi, produced a significant increase in the lifespan in wild type worms ( García-Casas et al, 2018 ; 2021a ).…”

Lighting Up Ca2+ Dynamics in Animal Models

“…The two most broadly used Ca 2+ sensors in C. elegans are GCaMPs and FRET-based cameleons, the most frequently expressed in neurons or muscular cells [44,[212][213][214], alone or under the optogenetic manipulation of neuronal activity [215]. Although the majority of the studies in C. elegans have been performed using untargeted probes expressed in the cytosol, relevant examples of Ca 2+ sensors expressed in organelles exist, e.g., mito-chondria [216][217][218]. Recently, advanced approaches allowed whole-brain Ca 2+ imaging, in which about 100 neurons were simultaneously monitored in moving worms [219,220].…”