{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zhang R"],"funding":["Ministry of Health, Labour and Welfare","National Center of Neurology and Psychiatry","Japan Agency for Medical Research and Development","THERS Interdisciplinary Frontier Next Generation Researcher Project","Nagoya University","Japan Society for the Promotion of Science"],"pagination":["dmm050768"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11554261"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["17(8)"],"pubmed_abstract":["Pathogenic variants in GFPT1, encoding a key enzyme to synthesize UDP-N-acetylglucosamine (UDP-GlcNAc), cause congenital myasthenic syndrome (CMS). We made a knock-in (KI) mouse model carrying a frameshift variant in Gfpt1 exon 9, simulating that found in a patient with CMS. As Gfpt1 exon 9 is exclusively expressed in striated muscles, Gfpt1-KI mice were deficient for Gfpt1 only in skeletal muscles. In Gfpt1-KI mice, (1) UDP-HexNAc, CMP-NeuAc and protein O-GlcNAcylation were reduced in skeletal muscles; (2) aged Gfpt1-KI mice showed poor exercise performance and abnormal neuromuscular junction structures; and (3) markers of the unfolded protein response (UPR) were elevated in skeletal muscles. Denervation-mediated enhancement of endoplasmic reticulum (ER) stress in Gfpt1-KI mice facilitated protein folding, ubiquitin-proteasome degradation and apoptosis, whereas autophagy was not induced and protein aggregates were markedly increased. Lack of autophagy was accounted for by enhanced degradation of FoxO1 by increased Xbp1-s/u proteins. Similarly, in Gfpt1-silenced C2C12 myotubes, ER stress exacerbated protein aggregates and activated apoptosis, but autophagy was attenuated. In both skeletal muscles in Gfpt1-KI mice and Gfpt1-silenced C2C12 myotubes, maladaptive UPR failed to eliminate protein aggregates and provoked apoptosis."],"journal":["Disease models & mechanisms"],"pubmed_title":["Muscle-specific lack of Gfpt1 triggers ER stress to alleviate misfolded protein accumulation."],"pmcid":["PMC11554261"],"funding_grant_id":["JP22K19269","JP23H02794","23FC1014","JP23K06412","JP23ek0109678","JPJSCCA202000007","JP21H02476","JP23K18273","5-6"],"pubmed_authors":["Farshadyeganeh P","Nakajima K","Ohno T","Takeda JI","Ohkawara B","Masuda A","Miyasaka Y","Ohno K","Ito M","Mori-Yoshimura M","Zhang S","Zhang R"],"additional_accession":[]},"is_claimable":false,"name":"Muscle-specific lack of Gfpt1 triggers ER stress to alleviate misfolded protein accumulation.","description":"Pathogenic variants in GFPT1, encoding a key enzyme to synthesize UDP-N-acetylglucosamine (UDP-GlcNAc), cause congenital myasthenic syndrome (CMS). We made a knock-in (KI) mouse model carrying a frameshift variant in Gfpt1 exon 9, simulating that found in a patient with CMS. As Gfpt1 exon 9 is exclusively expressed in striated muscles, Gfpt1-KI mice were deficient for Gfpt1 only in skeletal muscles. In Gfpt1-KI mice, (1) UDP-HexNAc, CMP-NeuAc and protein O-GlcNAcylation were reduced in skeletal muscles; (2) aged Gfpt1-KI mice showed poor exercise performance and abnormal neuromuscular junction structures; and (3) markers of the unfolded protein response (UPR) were elevated in skeletal muscles. Denervation-mediated enhancement of endoplasmic reticulum (ER) stress in Gfpt1-KI mice facilitated protein folding, ubiquitin-proteasome degradation and apoptosis, whereas autophagy was not induced and protein aggregates were markedly increased. Lack of autophagy was accounted for by enhanced degradation of FoxO1 by increased Xbp1-s/u proteins. Similarly, in Gfpt1-silenced C2C12 myotubes, ER stress exacerbated protein aggregates and activated apoptosis, but autophagy was attenuated. In both skeletal muscles in Gfpt1-KI mice and Gfpt1-silenced C2C12 myotubes, maladaptive UPR failed to eliminate protein aggregates and provoked apoptosis.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Aug","modification":"2025-04-04T12:01:26.205Z","creation":"2025-04-04T12:01:26.205Z"},"accession":"S-EPMC11554261","cross_references":{"pubmed":["38903011"],"doi":["10.1242/dmm.050768"]}}