Abstract:Background:In skeletal muscle, diverse stresses induce the transcription factor ATF4, which promotes muscle atrophy by an unknown mechanism. Results: ATF4 causes muscle atrophy by inducing Gadd45a, which reprograms myonuclear gene expression to repress antiatrophy mechanisms and induce pro-atrophy mechanisms. Conclusion: Gadd45a is a critical stress-induced mediator of muscle atrophy. Significance: The ATF4/Gadd45a pathway is a potential therapeutic target in atrophic muscle.
“…PERK deficiency in mice results in diabetes mellitus, skeletal dysplasias, and growth retardation [23,24], whereas ATF4 deficiency in mice causes microphthalmia [25,26], anemia [27], and bone angiogenesis deficits [28]. Interestingly, ATF4 deficiency protects mice from ER-stress-induced tissue damage [29][30][31]. Similar protective phenotypes were also observed in CHOP deficient mice [16,32,33].…”
Abstract:The endoplasmic reticulum (ER) plays important roles in coordinating protein biosynthesis and secretion in the cell. Accumulation of misfolded and/or unfolded proteins in the ER causes ER stress and the so-called unfolded protein response (UPR). The UPR alleviates ER stress through blocking protein synthesis and activating expression of chaperone genes, whereas prolonged UPR could induce cell death. Recent research has showed that ER stress and UPR are involved in hearing loss. Accordingly, animal experiments showed that chemical chaperones or ER stress inducers alleviate environment-related hearing loss, whereas ER stress inhibitor has been used to treat certain types of hereditary deafness. Further investigations are needed to fully understand the detailed mechanisms of how ER stress contributes to the loss of auditory function, which will help us to eventually develop ER-stress-related treatment of various types of deafness.
“…PERK deficiency in mice results in diabetes mellitus, skeletal dysplasias, and growth retardation [23,24], whereas ATF4 deficiency in mice causes microphthalmia [25,26], anemia [27], and bone angiogenesis deficits [28]. Interestingly, ATF4 deficiency protects mice from ER-stress-induced tissue damage [29][30][31]. Similar protective phenotypes were also observed in CHOP deficient mice [16,32,33].…”
Abstract:The endoplasmic reticulum (ER) plays important roles in coordinating protein biosynthesis and secretion in the cell. Accumulation of misfolded and/or unfolded proteins in the ER causes ER stress and the so-called unfolded protein response (UPR). The UPR alleviates ER stress through blocking protein synthesis and activating expression of chaperone genes, whereas prolonged UPR could induce cell death. Recent research has showed that ER stress and UPR are involved in hearing loss. Accordingly, animal experiments showed that chemical chaperones or ER stress inducers alleviate environment-related hearing loss, whereas ER stress inhibitor has been used to treat certain types of hereditary deafness. Further investigations are needed to fully understand the detailed mechanisms of how ER stress contributes to the loss of auditory function, which will help us to eventually develop ER-stress-related treatment of various types of deafness.
“…Atf4 conditional KO ( lox/lox ) mice and SMMHC-Cre ER(T2) mice were generated as previously described (10,49,50). SMMHC-Cre/GFP global Atf4 +/-and DBA/2J mice were obtained from The Jackson Laboratory (51,52).…”
“…1, A and B). GADD45A responds to cell stress and regulates anabolic signaling and energy homeostasis (19). P21 induces cell cycle arrest (30) and suppresses proliferation of multiple cell types in the skeletal muscle tissue (6); downstream, p21-activated kinase enhances cytoskeletal remodeling and glucose uptake (73).…”
Rowlands DS, Nelson AR, Raymond F, Metairon S, Mansourian R, Clarke J, Stellingwerff T, Phillips SM. Protein-leucine ingestion activates a regenerative inflammo-myogenic transcriptome in skeletal muscle following intense endurance exercise.
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