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

Paniz Farshadyeganeh; Mohammad Nazim; Ruchen Zhang; Bisei Ohkawara; Kazuki Nakajima; Mohammad Alinoor Rahman; Farhana Nasrin; Mikako Ito; Jun-Ichi Takeda; Kenji Ohe; Yuki Miyasaka; Tamio Ohno; Akio Masuda; Kinji Ohno

doi:10.1016/j.isci.2023.107746

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

iScience. 2023 Aug 26;26(10):107746. doi: 10.1016/j.isci.2023.107746. eCollection 2023 Oct 20.

Authors

Paniz Farshadyeganeh¹, Mohammad Nazim^{1

2}, Ruchen Zhang¹, Bisei Ohkawara¹, Kazuki Nakajima³, Mohammad Alinoor Rahman^{1

4}, Farhana Nasrin^{1

4}, Mikako Ito¹, Jun-Ichi Takeda¹, Kenji Ohe^{1

5}, Yuki Miyasaka⁶, Tamio Ohno⁶, Akio Masuda¹, Kinji Ohno¹

Affiliations

¹ Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
² Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Institute for Glyco-core Research (iGCORE), Gifu University, Gifu 501-1193, Japan.
⁴ Department of Biochemistry and Molecular Biology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72205, USA.
⁵ Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
⁶ Division of Experimental Animals, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

Abstract

Glutamine:fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP). A 54-bp exon 9 of GFPT1 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 GFPT1 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.

Keywords: Biochemistry; Biological sciences; Physiology.