scholarly journals mTORC1 Crosstalk With Stress Granules in Aging and Age-Related Diseases

2021 ◽  
Vol 2 ◽  
Author(s):  
Marti Cadena Sandoval ◽  
Alexander Martin Heberle ◽  
Ulrike Rehbein ◽  
Cecilia Barile ◽  
José Miguel Ramos Pittol ◽  
...  
Keyword(s):  
Growth Factor ◽  
Genomic Instability ◽  
Dynamic Process ◽  
Stress Granules ◽  
Telomere Shortening ◽  
Cellular Survival ◽  
Mechanistic Target Of Rapamycin ◽  
Age Related ◽  
Stress Signals ◽  
Complex Signaling

The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a master regulator of metabolism and aging. A complex signaling network converges on mTORC1 and integrates growth factor, nutrient and stress signals. Aging is a dynamic process characterized by declining cellular survival, renewal, and fertility. Stressors elicited by aging hallmarks such as mitochondrial malfunction, loss of proteostasis, genomic instability and telomere shortening impinge on mTORC1 thereby contributing to age-related processes. Stress granules (SGs) constitute a cytoplasmic non-membranous compartment formed by RNA-protein aggregates, which control RNA metabolism, signaling, and survival under stress. Increasing evidence reveals complex crosstalk between the mTORC1 network and SGs. In this review, we cover stressors elicited by aging hallmarks that impinge on mTORC1 and SGs. We discuss their interplay, and we highlight possible links in the context of aging and age-related diseases.

G3BP1 tethers the TSC complex to lysosomes and suppresses mTORC1 in the absence of stress granules

2020 ◽  
Author(s):  
Mirja T. Prentzell ◽  
Ulrike Rehbein ◽  
Marti Cadena Sandoval ◽  
Ann-Sofie De Meulemeester ◽  
Ralf Baumeister ◽  
...  
Keyword(s):  
Epileptiform Activity ◽  
Stress Granules ◽  
List Type ◽  
Protein Assemblies ◽  
Core Component ◽  
Cellular Survival ◽  
Mechanistic Target Of Rapamycin ◽  
Mtorc1 Signaling ◽  
Signaling Axis ◽  
Bona Fide

SummaryG3BP1 (Ras GTPase-activating protein-binding protein 1) is widely recognized as a core component of stress granules (SG), non-membranous RNA-protein-assemblies required for cellular survival under stress. We report that in the absence of SG, G3BP1 acts as lysosomal anchor of the Tuberous Sclerosis Complex (TSC) protein complex. By tethering the TSC complex to lysosomes, G3BP1 suppresses signaling through the metabolic master regulator mTORC1 (mechanistic target of rapamycin complex 1). Like the known TSC complex subunits, G3BP1 suppresses phenotypes related to mTORC1 hyperactivity in the context of tumors and neuronal dysfunction. Thus, G3BP1 is not only a core component of SG but also a key element of lysosomal TSC-mTORC1 signaling.HighlightsThe bona fide stress granule component G3BP1 is a key element of the TSC-mTORC1 signaling axis.tethers the TSC complex to lysosomes.prevents mTORC1 hyperactivation by metabolic stimuli.suppresses mTORC1-driven cancer cell motility and epileptiform activity.Graphical Abstract

scholarly journals Lysosomes, Autophagy, and Hormesis in Cell Physiology, Pathology, and Age-Related Disease

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582093422 ◽  
Author(s):  
Michael N. Moore
Keyword(s):  
Intracellular Signaling ◽  
Adenosine Monophosphate ◽  
Target Of Rapamycin ◽  
Cell Physiology ◽  
Mechanistic Target Of Rapamycin ◽  
Age Related ◽  
Mechanistic Basis ◽  
The Many ◽  
Mtor Complex 1

Autophagy has been strongly linked with hormesis, however, it is only relatively recently that the mechanistic basis underlying this association has begun to emerge. Lysosomal autophagy is a group of processes that degrade proteins, protein aggregates, membranes, organelles, segregated regions of cytoplasm, and even parts of the nucleus in eukaryotic cells. These degradative processes are evolutionarily very ancient and provide a survival capability for cells that are stressed or injured. Autophagy and autophagic dysfunction have been linked with many aspects of cell physiology and pathology in disease processes; and there is now intense interest in identifying various therapeutic strategies involving its regulation. The main regulatory pathway for augmented autophagy is the mechanistic target of rapamycin (mTOR) cell signaling, although other pathways can be involved, such as 5′-adenosine monophosphate-activated protein kinase. Mechanistic target of rapamycin is a key player in the many highly interconnected intracellular signaling pathways and is responsible for the control of cell growth among other processes. Inhibition of mTOR (specifically dephosphorylation of mTOR complex 1) triggers augmented autophagy and the search is on the find inhibitors that can induce hormetic responses that may be suitable for treating many diseases, including many cancers, type 2 diabetes, and age-related neurodegenerative conditions.

scholarly journals Gait disturbances and muscle dysfunction in fibroblast growth factor 2 knockout mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
C. Homer-Bouthiette ◽  
L. Xiao ◽  
Marja M. Hurley
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscle Strength ◽  
Fibroblast Growth Factor ◽  
Muscle Function ◽  
Fibroblast Growth Factor 2 ◽  
Fibroblast Growth ◽  
Skeletal Muscle Function ◽  
Age Related ◽  
Gait Disturbances

AbstractFibroblast growth factor 2 (FGF2) is important in musculoskeletal homeostasis, therefore the impact of reduction or Fgf2 knockout on skeletal muscle function and phenotype was determined. Gait analysis as well as muscle strength testing in young and old WT and Fgf2KO demonstrated age-related gait disturbances and reduction in muscle strength that were exacerbated in the KO condition. Fgf2 mRNA and protein were significantly decreased in skeletal muscle of old WT compared with young WT. Muscle fiber cross-sectional area was significantly reduced with increased fibrosis and inflammatory infiltrates in old WT and Fgf2KO vs. young WT. Inflammatory cells were further significantly increased in old Fgf2KO compared with old WT. Lipid-related genes and intramuscular fat was increased in old WT and old Fgf2KO with a further increase in fibro-adipocytes in old Fgf2KO compared with old WT. Impaired FGF signaling including Increased β-Klotho, Fgf21 mRNA, FGF21 protein, phosphorylated FGF receptors 1 and 3, was observed in old WT and old Fgf2KO. MAPK/ ERK1/2 was significantly increased in young and old Fgf2KO. We conclude that Fgf2KO, age-related decreased FGF2 in WT mice, and increased FGF21 in the setting of impaired Fgf2 expression likely contribute to impaired skeletal muscle function and sarcopenia in mice.

TREATMENT OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION PATIENTS WITH VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS IN EVERYDAY PRACTICE

Retina ◽  
2018 ◽  
Vol 38 (6) ◽  
pp. 1134-1144 ◽  
Author(s):  
Christoph Ehlken ◽  
Thomas Wilke ◽  
Ulrike Bauer-Steinhusen ◽  
Hansjürgen T. Agostini ◽  
Zoran Hasanbasic ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Everyday Practice ◽  
Vascular Endothelial ◽  
Age Related ◽  
Endothelial Growth Factor
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