Farshadyeganeh Paniz, Nazim Mohammad, Zhang Ruchen, Ohkawara Bisei, Nakajima Kazuki, Rahman Mohammad Alinoor, Nasrin Farhana, Ito Mikako, Takeda Jun-Ichi, Ohe Kenji, Miyasaka Yuki, Ohno Tamio, Masuda Akio, Ohno Kinji
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
iScience. 2023 Aug 26;26(10):107746. doi: 10.1016/j.isci.2023.107746. eCollection 2023 Oct 20.
Glutamine:fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP). A 54-bp exon 9 of is specifically included in skeletal and cardiac muscles to generate a long isoform of GFPT1 (GFPT1-L). We showed that SRSF1 and Rbfox1/2 cooperatively enhance, and hnRNP H/F suppresses, the inclusion of human exon 9 by modulating recruitment of U1 snRNP. Knockout (KO) of GFPT1-L in skeletal muscle markedly increased the amounts of GFPT1 and UDP-HexNAc, which subsequently suppressed the glycolytic pathway. Aged KO mice showed impaired insulin-mediated glucose uptake, as well as muscle weakness and fatigue likely due to abnormal formation and maintenance of the neuromuscular junction. Taken together, GFPT1-L is likely to be acquired in evolution in mammalian striated muscles to attenuate the HBP for efficient glycolytic energy production, insulin-mediated glucose uptake, and the formation and maintenance of the neuromuscular junction.
果糖-6-磷酸转氨酶1（GFPT1）是己糖胺生物合成途径（HBP）的限速酶。GFPT1的一个54个碱基对的外显子9特异性地包含在骨骼肌和心肌中，以产生GFPT1的长异构体（GFPT1-L）。我们发现，SRSF1和Rbfox1/2协同增强，而hnRNP H/F通过调节U1 snRNP的募集来抑制人外显子9的包含。骨骼肌中GFPT1-L的敲除（KO）显著增加了GFPT1和UDP-HexNAc的量，随后抑制了糖酵解途径。老年KO小鼠表现出胰岛素介导的葡萄糖摄取受损，以及可能由于神经肌肉接头异常形成和维持导致的肌肉无力和疲劳。综上所述，GFPT1-L可能是在哺乳动物横纹肌的进化过程中获得的，以减弱HBP，从而实现高效的糖酵解能量产生、胰岛素介导的葡萄糖摄取以及神经肌肉接头的形成和维持。
