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dc.contributor.authorRussell, Sarah J
dc.contributor.authorSchneider, Martin F
dc.date.accessioned2020-11-18T16:32:38Z
dc.date.available2020-11-18T16:32:38Z
dc.date.issued2020-08-31
dc.identifier.urihttp://hdl.handle.net/10713/14106
dc.description.abstractMuscle atrophy is regulated by the balance between protein degradation and synthesis. FOXO1, a transcription factor, helps to determine this balance by activating pro-atrophic gene transcription when present in muscle fiber nuclei. Foxo1 nuclear efflux is promoted by AKT-mediated Foxo1 phosphorylation, eliminating FOXO1's atrophy-promoting effect. AKT activation can be promoted by insulin-like growth factor 1 (IGF1) or insulin via a pathway including IGF1 or insulin, phosphatidylinositol 3-kinase, and AKT. We used confocal fluorescence time-lapse imaging of FOXO1-GFP in adult isolated living muscle fibers maintained in culture to explore the effects of IGF1 and insulin on FOXO1-GFP nuclear efflux with and without pharmacological inhibitors. We observed that although AKT inhibitor blocks the IGF1- or insulin-induced effect on FOXO1 nuclear efflux, phosphatidylinositol 3-kinase inhibitors, which we show to be effective in these fibers, do not. We also found that inhibition of the protein kinase ACK1 or ATM contributes to the suppression of FOXO1 nuclear efflux after IGF1. These results indicate a novel pathway that has been unexplored in the IGF1- or insulin-induced regulation of FOXO1 and present information useful both for therapeutic interventions for muscle atrophy and for further investigative areas into insulin insensitivity and type 2 diabetes.en_US
dc.description.urihttps://doi.org/10.1074/jbc.RA120.013634en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc.en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.rights© 2020 Russell and Schneider.en_US
dc.subjectAkten_US
dc.subjectAkt PKBen_US
dc.subjectFOXOen_US
dc.subjectFoxo1en_US
dc.subjectIGF-1en_US
dc.subjectinsulinen_US
dc.subjectinsulin-like growth factor (IGF)en_US
dc.subjectnuclear translocationen_US
dc.subjectprotein phosphorylationen_US
dc.subjectskeletal muscleen_US
dc.titleAlternative signaling pathways from IGF1 or insulin to AKT activation and FOXO1 nuclear efflux in adult skeletal muscle fibersen_US
dc.typeArticleen_US
dc.identifier.doi10.1074/jbc.RA120.013634
dc.identifier.pmid32868454
dc.source.volume295
dc.source.issue45
dc.source.beginpage15292
dc.source.endpage15306
dc.source.countryUnited States


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