RT info:eu-repo/semantics/doctoralThesis
T1 Calcium signaling modulators: a novel pharmacological intervention to delay aging in Caenorhabditis elegans
A1 García Casas, Paloma
A2 Universidad de Valladolid. Facultad de Medicina
K1 Calcio
K1 Caenorhabditis elegans
K1 32 Ciencias Médicas
AB Ca2+ is a second messenger that affects nearly every aspect or cellular lifeincluding muscle contraction, neuronal secretion and cell proliferation anddifferentiation. The dysregulation of the cellular toolkit that controls andmaintains Ca2+ homeostasis has been linked to the physiopathology of the agingprocess including neurodegeneration. Caenorhabditis elegans has been proven tobe an excellent model organism to study aging and neurodegeneration due to theconservation of numerous signaling pathways that have been proven to modulateaging, and the availability of several models of neurodegenerative diseases.Moreover, the interrelationship between aging and Ca2+ signaling can be studiedin the worms because of their transparent cuticle that allows to perform in vivoCa2+ dynamics studies throughout the whole life of the organisms.The metabolic pathways that are known to regulate aging in C. elegans arethe so called nutrient sensing pathways. All these pathways, that are conserved inmammals, are able to respond to changes in nutrient availability that, in the end,affect the longevity of the worms. These pathways are the insulin/insulin-likegrowthfactor (IGF-1) signaling pathway (IIS), the mechanistic target of rapamycin(mTOR) signaling pathway, the adenosine monophosphate-activated proteinkinase (AMPK) pathway, and the sirtuins pathway. Although not muchinformation about how intracellular Ca2+ regulates these pathways, there is someevidence that suggests that Ca2+ might be implicated in the modulation of nutrientsensing pathways activities.This thesis has focused in the study of the interrelationship between Ca2+signaling and nutrient sensing pathways, and its possible effects in the agingprocess through two different pharmacological approaches: the submaximalinhibition of sarco-endoplasmic reticulum calcium-ATPase (SERCA) using 2,5-BHQand thapsigargin, and the submaximal inhibition of the mitochondrial Na+/Ca2+exchanger using CGP37157.SERCA refills the endoplasmic reticulum (ER) with Ca2+ up to the millimolarrange being the main controller of the ER [Ca2+] level, implicated in the modulationof cytosolic Ca2+ signaling and ER-mitochondria Ca2+ transfer. In this work it hasbeen proven that the submaximal inhibition of SERCA with 2,5-BHQ andthapsigargin induced an increase in the lifespan of C. elegans worms and that thiseffect was mediated by the modulation of mTOR and AMPK signaling pathways.Moreover, it was also discarded that the effect was mediated by the activation ofthe ER stress response.CGP37157 is a benzothiazepine with neuroprotective effects in several in vitromodels of excitotoxicity involving dysregulation of intracellular Ca2+ homeostasis.CGP37157 has been used for decades as an inhibitor of the mitochondrial Na+/Ca2+20 exchanger (mNCX), although several off targets have been described. Throughoutthis thesis, the effects of CGP37157 in C. elegans healthspan, as well as its possiblemodulation of nutrient sensing pathways and Ca2+ dynamics, have been explored.Our results show that the treatment with CGP37157 is able to induce an increasein C. elegans life expectancy through the modulation of the mTOR and IISsignaling pathways. Moreover, it was proven that a functional electron transportchain activity was required for CGP37157 to exert its effects, and that CGP37157treatment induced changes in intracellular Ca2+, including cytosolic andmitochondrial Ca2+ dynamics changes in two different muscular systems, thepharynx and the vulva. Finally, the changes induced by CGP37157 also caused animprovement in worm’s locomotion and muscle function delaying the sarcopeniaprocess and improving mitochondrial integrity and organization in C. elegans bodywall muscle cells.In conclusion, this work has described two novel pharmacologicalinterventions that improve C. elegans lifespan through the modulation of Ca2+signaling in a different manner. These results outline the possible therapeuticeffects of both SERCA inhibitors and CGP37157 in the aging process, and theimportance of Ca2+ signaling in the regulation and evolution of aging relatedphysiopathology.
YR 2020
FD 2020
LK http://uvadoc.uva.es/handle/10324/43492
UL http://uvadoc.uva.es/handle/10324/43492
LA eng
NO Departamento de Bioquímica y Biología Molecular y Fisiología
DS UVaDOC
RD 24-nov-2024