title: CUG-BP1 regulates RyR1 ASI alternative splicing in skeletal muscle atrophy.
abstract: RNA binding protein is identified as an important mediator of aberrant alternative splicing in muscle atrophy. The altered splicing of calcium channels, such as ryanodine receptors (RyRs), plays an important role in impaired excitation-contraction (E-C) coupling in muscle atrophy; however, the regulatory mechanisms of ryanodine receptor 1 (RyR1) alternative splicing leading to skeletal muscle atrophy remains to be investigated. In this study we demonstrated that CUG binding protein 1 (CUG-BP1) was up-regulated and the alternative splicing of RyR1 ASI (exon70) was aberrant during the process of neurogenic muscle atrophy both in human patients and mouse models. The gain and loss of function experiments in vivo demonstrated that altered splicing pattern of RyR1 ASI was directly mediated by an up-regulated CUG-BP1 function. Furthermore, we found that CUG-BP1 affected the calcium release activity in single myofibers and the extent of atrophy was significantly reduced upon gene silencing of CUG-BP1 in atrophic muscle. These findings improve our understanding of calcium signaling related biological function of CUG-BP1 in muscle atrophy. Thus, we provide an intriguing perspective of involvement of mis-regulated RyR1 splicing in muscular disease.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.|University of the Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Tang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan 48201.
authors.forename: Bin
authors.initials: B
authors.lastname: Wei
authors.affiliation: University of the Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Guo
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.|University of the Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.|University of the Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Neurology, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D000067879:CELF1 Protein / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D009133:Muscular Atrophy / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis / Q000235:genetics*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium