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000300710 1001_ $$00000-0002-3485-1597$$aConjard-Duplany, Agnès$$b0
000300710 245__ $$aMuscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways.
000300710 260__ $$aCham (ZG)$$bSpringer International Publishing AG$$c2025
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000300710 520__ $$aBalanced mTOR activity and iron levels are crucial for muscle integrity, with evidence suggesting mTOR regulates cellular iron homeostasis. In this study, we investigated iron metabolism in muscle-specific mTOR knockout mice (mTORmKO) and its relation to their myopathy. The mTORmKO mice exhibited distinct iron content patterns across muscle types and ages. Slow-twitch soleus muscles initially showed reduced iron levels in young mice, which increased with the dystrophy progression but remained within control ranges. In contrast, the less affected fast-twitch muscles maintained near-normal iron levels from a young age. Interestingly, both mTORmKO muscle types exhibited iron metabolism markers indicative of iron excess, including decreased transferrin receptor 1 (TFR1) and increased levels of ferritin (FTL) and ferroportin (FPN) proteins. Paradoxically, these changes were accompanied by downregulated Ftl and Fpn mRNA levels, indicating post-transcriptional regulation. This discordant regulation resulted from disruption of key iron metabolism pathways, including NRF2/NFE2L2, HIFs, and AKT/PKB signaling. Mechanistically, mTOR deficiency impaired transcriptional regulation of iron-related genes mediated by NRF2 and HIFs. Furthermore, it triggered ferritin accumulation through two NRF2 mechanisms: (1) derepression of ferritin translation via suppression of the FBXL5-IRP axis, and (2) autophagosomal sequestration driven by NCOA4-dependent ferritin targeting to autophagosomes, coupled with age-related impairments of autophagy linked to chronic AKT/PKB activation. Three-week spermidine supplementation in older mTORmKO mice was associated with normalized AKT/PKB-FOXO signaling, increased endolysosomal FTL and reduced total FTL levels in the dystrophic soleus muscle. These findings underscore mTOR's crucial role in skeletal muscle iron metabolism and suggest spermidine as a potential strategy to address impaired ferritinophagy due to autophagy blockade in dystrophic muscle.
000300710 536__ $$0G:(DE-HGF)POF4-314$$a314 - Immunologie und Krebs (POF4-314)$$cPOF4-314$$fPOF IV$$x0
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000300710 650_7 $$2Other$$aAutophagy
000300710 650_7 $$2Other$$aDystrophy
000300710 650_7 $$2Other$$aGlycogen
000300710 650_7 $$2Other$$aIron-sulfur cluster
000300710 650_7 $$2Other$$aMyoglobin
000300710 650_7 $$2Other$$aOxidative stress
000300710 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aTOR Serine-Threonine Kinases
000300710 650_7 $$0E1UOL152H7$$2NLM Chemicals$$aIron
000300710 650_7 $$09007-73-2$$2NLM Chemicals$$aFerritins
000300710 650_7 $$2NLM Chemicals$$aNF-E2-Related Factor 2
000300710 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProto-Oncogene Proteins c-akt
000300710 650_7 $$0EC 2.7.1.1$$2NLM Chemicals$$amTOR protein, mouse
000300710 650_7 $$2NLM Chemicals$$aFerroportin
000300710 650_7 $$2NLM Chemicals$$aNfe2l2 protein, mouse
000300710 650_7 $$2NLM Chemicals$$aCation Transport Proteins
000300710 650_7 $$2NLM Chemicals$$aReceptors, Transferrin
000300710 650_7 $$2NLM Chemicals$$aBasic Helix-Loop-Helix Transcription Factors
000300710 650_7 $$2NLM Chemicals$$aNuclear Receptor Coactivators
000300710 650_2 $$2MeSH$$aAnimals
000300710 650_2 $$2MeSH$$aTOR Serine-Threonine Kinases: metabolism
000300710 650_2 $$2MeSH$$aTOR Serine-Threonine Kinases: genetics
000300710 650_2 $$2MeSH$$aIron: metabolism
000300710 650_2 $$2MeSH$$aFerritins: metabolism
000300710 650_2 $$2MeSH$$aFerritins: genetics
000300710 650_2 $$2MeSH$$aNF-E2-Related Factor 2: metabolism
000300710 650_2 $$2MeSH$$aHomeostasis
000300710 650_2 $$2MeSH$$aSignal Transduction
000300710 650_2 $$2MeSH$$aProto-Oncogene Proteins c-akt: metabolism
000300710 650_2 $$2MeSH$$aMice, Knockout
000300710 650_2 $$2MeSH$$aMuscle, Skeletal: metabolism
000300710 650_2 $$2MeSH$$aMice
000300710 650_2 $$2MeSH$$aAutophagy
000300710 650_2 $$2MeSH$$aFerroportin
000300710 650_2 $$2MeSH$$aCation Transport Proteins: metabolism
000300710 650_2 $$2MeSH$$aCation Transport Proteins: genetics
000300710 650_2 $$2MeSH$$aReceptors, Transferrin: metabolism
000300710 650_2 $$2MeSH$$aBasic Helix-Loop-Helix Transcription Factors: metabolism
000300710 650_2 $$2MeSH$$aMice, Inbred C57BL
000300710 650_2 $$2MeSH$$aNuclear Receptor Coactivators: metabolism
000300710 650_2 $$2MeSH$$aMale
000300710 7001_ $$00000-0003-3435-5785$$aOsseni, Alexis$$b1
000300710 7001_ $$00000-0002-9161-9997$$aLamboux, Aline$$b2
000300710 7001_ $$00000-0002-7627-7984$$aMouradian, Sandrine$$b3
000300710 7001_ $$00000-0001-9447-5178$$aPicard, Flavien$$b4
000300710 7001_ $$00000-0002-4163-0231$$aMoncollin, Vincent$$b5
000300710 7001_ $$aAngleraux, Céline$$b6
000300710 7001_ $$aDorel-Dubois, Tiphaine$$b7
000300710 7001_ $$00000-0003-4711-2248$$aPuccio, Hélène$$b8
000300710 7001_ $$00000-0003-3214-5880$$aLeblanc, Pascal$$b9
000300710 7001_ $$0P:(DE-He78)00eb6e35f6edc7e5fcb2aacc7a21f891$$aGaly, Bruno$$b10
000300710 7001_ $$00000-0002-9236-4834$$aBalter, Vincent$$b11
000300710 7001_ $$00000-0001-6600-503X$$aSchaeffer, Laurent$$b12
000300710 7001_ $$00000-0001-9031-1184$$aGangloff, Yann-Gaël$$b13
000300710 773__ $$0PERI:(DE-600)1458497-9$$a10.1007/s00018-025-05695-9$$gVol. 82, no. 1, p. 178$$n1$$p178$$tCellular and molecular life sciences$$v82$$x1420-682X$$y2025
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