FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4309277379> ?p ?o ?g. }

• W4309277379 endingPage "213" @default.
• W4309277379 startingPage "198" @default.
• W4309277379 abstract "Chronic mTORC1 activation in skeletal muscle is linked with age-associated loss of muscle mass and strength, known as sarcopenia. Genetic activation of mTORC1 by conditionally ablating mTORC1 upstream inhibitor TSC1 in skeletal muscle accelerates sarcopenia development in adult mice. Conversely, genetic suppression of mTORC1 downstream effectors of protein synthesis delays sarcopenia in natural aging mice. mTORC1 promotes protein synthesis by activating ribosomal protein S6 kinases (S6Ks) and inhibiting eIF4E-binding proteins (4EBPs). Whole-body knockout of S6K1 or muscle-specific over-expression of a 4EBP1 mutant transgene (4EBP1mt), which is resistant to mTORC1-mediated inhibition, ameliorates muscle loss with age and preserves muscle function by enhancing mitochondria activities, despite both transgenic mice showing retarded muscle growth at a young age. Why repression of mTORC1-mediated protein synthesis can mitigate progressive muscle atrophy and dysfunction with age remains unclear.Mice with myofiber-specific knockout of TSC1 (TSC1mKO), in which mTORC1 is hyperactivated in fully differentiated myofibers, were used as a mouse model of sarcopenia. To elucidate the role of mTORC1-mediated protein synthesis in regulating muscle mass and physiology, we bred the 4EBP1mt transgene or S6k1 floxed mice into the TSC1mKO mouse background to generate 4EBP1mt-TSC1mKO or S6K1-TSC1mKO mice, respectively. Functional and molecular analyses were performed to assess their role in sarcopenia development.Here, we show that 4EBP1mt-TSC1mKO, but not S6K1-TSC1mKO, preserved muscle mass (36.7% increase compared with TSC1mKO, P < 0.001) and strength (36.8% increase compared with TSC1mKO, P < 0.01) at the level of control mice. Mechanistically, 4EBP1 activation suppressed aberrant protein synthesis (two-fold reduction compared with TSC1mKO, P < 0.05) and restored autophagy flux without relieving mTORC1-mediated inhibition of ULK1, an upstream activator of autophagosome initiation. We discovered a previously unidentified phenotype of lysosomal failure in TSC1mKO mouse muscle, in which the lysosomal defect was also conserved in the naturally aged mouse muscle, whereas 4EBP1 activation enhanced lysosomal protease activities to compensate for impaired autophagy induced by mTORC1 hyperactivity. Consequently, 4EBP1 activation relieved oxidative stress to prevent toxic aggregate accumulation (0.5-fold reduction compared with TSC1mKO, P < 0.05) in muscle and restored mitochondrial homeostasis and function.We identify 4EBP1 as a communication hub coordinating protein synthesis and degradation to protect proteostasis, revealing therapeutic potential for activating lysosomal degradation to mitigate sarcopenia." @default.
• W4309277379 created "2022-11-25" @default.
• W4309277379 creator A5009027905 @default.
• W4309277379 creator A5015164997 @default.
• W4309277379 creator A5015969093 @default.
• W4309277379 creator A5024081302 @default.
• W4309277379 creator A5024813315 @default.
• W4309277379 creator A5025570443 @default.
• W4309277379 creator A5033262286 @default.
• W4309277379 creator A5035374125 @default.
• W4309277379 creator A5042792401 @default.
• W4309277379 creator A5046318374 @default.
• W4309277379 creator A5051704856 @default.
• W4309277379 creator A5068369242 @default.
• W4309277379 creator A5071776616 @default.
• W4309277379 creator A5074408596 @default.
• W4309277379 creator A5091560850 @default.
• W4309277379 creator A5054416615 @default.
• W4309277379 date "2022-11-17" @default.
• W4309277379 modified "2023-09-26" @default.
• W4309277379 title "Activation of <scp>eIF4E</scp>‐binding‐protein‐1 rescues <scp>mTORC1</scp>‐induced sarcopenia by expanding lysosomal degradation capacity" @default.
• W4309277379 cites W1938485232 @default.
• W4309277379 cites W1966082815 @default.
• W4309277379 cites W1979298497 @default.
• W4309277379 cites W1998319919 @default.
• W4309277379 cites W1998763810 @default.
• W4309277379 cites W2002226709 @default.
• W4309277379 cites W2014892893 @default.
• W4309277379 cites W2020978481 @default.
• W4309277379 cites W2027797630 @default.
• W4309277379 cites W2050878478 @default.
• W4309277379 cites W2057741310 @default.
• W4309277379 cites W2060129186 @default.
• W4309277379 cites W2065952016 @default.
• W4309277379 cites W2080094749 @default.
• W4309277379 cites W2083919459 @default.
• W4309277379 cites W2084107582 @default.
• W4309277379 cites W2088855154 @default.
• W4309277379 cites W2100428689 @default.
• W4309277379 cites W2107674876 @default.
• W4309277379 cites W2145390098 @default.
• W4309277379 cites W2149451793 @default.
• W4309277379 cites W2159664830 @default.
• W4309277379 cites W2164462432 @default.
• W4309277379 cites W2169812053 @default.
• W4309277379 cites W2314300835 @default.
• W4309277379 cites W2345178899 @default.
• W4309277379 cites W2402144501 @default.
• W4309277379 cites W2487409056 @default.
• W4309277379 cites W2527802977 @default.
• W4309277379 cites W2593816418 @default.
• W4309277379 cites W2749024777 @default.
• W4309277379 cites W2750504620 @default.
• W4309277379 cites W2765341183 @default.
• W4309277379 cites W2932576322 @default.
• W4309277379 cites W2939703826 @default.
• W4309277379 cites W2956198238 @default.
• W4309277379 cites W2984347228 @default.
• W4309277379 cites W3083833377 @default.
• W4309277379 cites W3108936441 @default.
• W4309277379 cites W4200379278 @default.
• W4309277379 cites W4309277379 @default.
• W4309277379 doi "https://doi.org/10.1002/jcsm.13121" @default.
• W4309277379 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36398408" @default.
• W4309277379 hasPublicationYear "2022" @default.
• W4309277379 type Work @default.
• W4309277379 citedByCount "4" @default.
• W4309277379 countsByYear W43092773792022 @default.
• W4309277379 countsByYear W43092773792023 @default.
• W4309277379 crossrefType "journal-article" @default.
• W4309277379 hasAuthorship W4309277379A5009027905 @default.
• W4309277379 hasAuthorship W4309277379A5015164997 @default.
• W4309277379 hasAuthorship W4309277379A5015969093 @default.
• W4309277379 hasAuthorship W4309277379A5024081302 @default.
• W4309277379 hasAuthorship W4309277379A5024813315 @default.
• W4309277379 hasAuthorship W4309277379A5025570443 @default.
• W4309277379 hasAuthorship W4309277379A5033262286 @default.
• W4309277379 hasAuthorship W4309277379A5035374125 @default.
• W4309277379 hasAuthorship W4309277379A5042792401 @default.
• W4309277379 hasAuthorship W4309277379A5046318374 @default.
• W4309277379 hasAuthorship W4309277379A5051704856 @default.
• W4309277379 hasAuthorship W4309277379A5054416615 @default.
• W4309277379 hasAuthorship W4309277379A5068369242 @default.
• W4309277379 hasAuthorship W4309277379A5071776616 @default.
• W4309277379 hasAuthorship W4309277379A5074408596 @default.
• W4309277379 hasAuthorship W4309277379A5091560850 @default.
• W4309277379 hasBestOaLocation W43092773791 @default.
• W4309277379 hasConcept C102230213 @default.
• W4309277379 hasConcept C104202773 @default.
• W4309277379 hasConcept C104317684 @default.
• W4309277379 hasConcept C105580179 @default.
• W4309277379 hasConcept C134018914 @default.
• W4309277379 hasConcept C141035611 @default.
• W4309277379 hasConcept C149364088 @default.
• W4309277379 hasConcept C161295673 @default.
• W4309277379 hasConcept C167414201 @default.
• W4309277379 hasConcept C2776214593 @default.
• W4309277379 hasConcept C2776263037 @default.

• next