Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme that participates in various cellular events, such as DNA repair and apoptosis. The functional diversity of GAPDH depends on its intracellular localization. Because AMP-activated protein kinase (AMPK) regulates the nuclear translocation of GAPDH in young cells and AMPK activity significantly increases during aging, we investigated whether altered AMPK activity is involved in the nuclear localization of GAPDH in senescent cells. Age-dependent nuclear translocation of GAPDH was confirmed by confocal laser scanning microscopy in human diploid fibroblasts (HDFs) and by immunohistochemical analysis in aged rat skin cells. Senescence-induced nuclear localization was reversed by lysophosphatidic acid but not by platelet-derived growth factor. The extracellular matrix from young cells also induced the nuclear export of GAPDH in senescent HDFs. An activator of AMPK, 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), increased the level of nuclear GAPDH, whereas an inhibitor of AMPK, Compound C, decreased the level of nuclear GAPDH in senescent HDFs. Transfection with AMPKα siRNA prevented nuclear translocation of GAPDH in senescent HDFs. The stimulatory effect of AICAR and serum depletion on GAPDH nuclear translocation was reduced in AMPKα1/α2-knockout mouse embryonic fibroblasts. Overall, increased AMPK activity may play a role in the senescence-associated nuclear translocation of GAPDH.
Highlights
Cellular senescence is a complex and heterogeneous process characterized by cell cycle arrest after a limited number of cell divisions
Nuclear localization of Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in senescent human diploid fibroblast (HDF) and skin cells of aged rats We investigated the intracellular distribution of GAPDH in young and senescent HDFs with population doubling (PD) of 16 and 72, respectively, by confocal laser scanning microscopy of immunostained HDFs
Because GAPDH was shown to translocate to the nucleus under various stress conditions, such as serum depletion [50] and oxidative stress [22], aging-associated growth signal deficits and oxidative stress may be involved in GAPDH nuclear translocation
Summary
Cellular senescence is a complex and heterogeneous process characterized by cell cycle arrest after a limited number of cell divisions. The gradual accumulation of senescent cells during aging can be associated with a progressive decline in physiological functions, promoting tissue damage and making proinflammatory environments favorable for various age-associated diseases, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases [2,3,4]. Cellular senescence is generally thought to be an absolute and irreversible process, the possibility of reversing agerelated decline in regenerative properties by exposure to a young systemic environment has been suggested [8]. Young and adult ECM improve cardiac function, whereas aged ECM accelerates the aging phenotype in cardiomyocytes [10], supporting the utilization of ECM-based cardiac regenerative medicines [11]
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