Splicing regulation of GFPT1 muscle-specific isoform and its roles in glucose metabolisms and neuromuscular junction,iScience

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Splicing regulation of GFPT1 muscle-specific isoform and its roles in glucose metabolisms and neuromuscular junction
iScience ( IF 4.6 ) Pub Date : 2023-08-26 , DOI: 10.1016/j.isci.2023.107746
Paniz Farshadyeganeh ₁ , Mohammad Nazim _{1,

2} , Ruchen Zhang ₁ , Bisei Ohkawara ₁ , Kazuki Nakajima ₃ , Mohammad Alinoor Rahman _{1,

4} , Farhana Nasrin _{1,

4} , Mikako Ito ₁ , Jun-Ichi Takeda ₁ , Kenji Ohe _{1,

5} , Yuki Miyasaka ₆ , Tamio Ohno ₆ , Akio Masuda ₁ , Kinji Ohno ₁

Affiliation

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.

中文翻译：

GFPT1肌肉特异性亚型的剪接调控及其在葡萄糖代谢和神经肌肉接头中的作用

谷氨酰胺：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。 54-bp 的外显子 9 专门包含在骨骼肌和心肌中，以生成 GFPT1 的长亚型 (GFPT1-L)。我们发现 SRSF1 和 Rbfox1/2 通过调节 U1 snRNP 的募集协同增强人类外显子 9 的包含，而 hnRNP H/F 则抑制人类外显子 9 的包含。骨骼肌中 GFPT1-L 的敲除 (KO) 显着增加了 GFPT1 和 UDP-HexNAc 的量，从而抑制了糖酵解途径。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的异常形成和维持而导致的肌肉无力和疲劳。总而言之，GFPT1-L 很可能是在哺乳动物横纹肌的进化过程中获得的，以减弱 HBP，从而有效地产生糖酵解能量、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。

更新日期：2023-08-26

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