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Skeletal muscle-specific Prmt1 deletion causes muscle atrophy via deregulation of the PRMT6-FOXO3 axis

Authors
Choi, SeriJeong, Hyeon-JuKim, HyebeenChoi, DaheeCho, Sung-ChunSeong, Je KyungKoo, Seung-HoiKang, Jong-Sun
Issue Date
3-6월-2019
Publisher
TAYLOR & FRANCIS INC
Keywords
Arginine methylation; FOXO3; muscle atrophy; PRMT1; PRMT6
Citation
AUTOPHAGY, v.15, no.6, pp.1069 - 1081
Indexed
SCIE
SCOPUS
Journal Title
AUTOPHAGY
Volume
15
Number
6
Start Page
1069
End Page
1081
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/64804
DOI
10.1080/15548627.2019.1569931
ISSN
1554-8627
Abstract
Protein arginine methyltransferases (PRMTs) have emerged as important regulators of skeletal muscle metabolism and regeneration. However, the direct roles of the various PRMTs during skeletal muscle remodeling remain unclear. Using skeletal muscle-specific prmt1 knockout mice, we examined the function and downstream targets of PRMT1 in muscle homeostasis. We found that muscle-specific PRMT1 deficiency led to muscle atrophy. PRMT1-deficient muscles exhibited enhanced expression of a macroautophagic/autophagic marker LC3-II, FOXO3 and muscle-specific ubiquitin ligases, TRIM63/MURF-1 and FBXO32, likely contributing to muscle atrophy. The mechanistic study reveals that PRMT1 regulates FOXO3 through PRMT6 modulation. In the absence of PRMT1, increased PRMT6 specifically methylates FOXO3 at arginine 188 and 249, leading to its activation. Finally, we demonstrate that PRMT1 deficiency triggers FOXO3 hyperactivation, which is abrogated by PRMT6 depletion. Taken together, PRMT1 is a key regulator for the PRMT6-FOXO3 axis in the control of autophagy and protein degradation underlying muscle maintenance.Abbreviations: Ad-RNAi: adenovirus-delivered small interfering RNA; AKT: thymoma viral proto-oncogene; AMPK: AMP-activated protein kinase; Baf A1: bafilomycin A(1); CSA: cross-sectional area; EDL: extensor digitorum longus; FBXO32: F-box protein 32; FOXO: forkhead box O; GAS: gatrocnemieus; HDAC: histone deacetylase; IGF: insulin-like growth factor; LAMP: lysosomal-associated membrane protein; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mKO: Mice with skeletal muscle-specific deletion of Prmt1; MTOR: mechanistic target of rapamycin kinase; MYH: myosin heavy chain; MYL1/MLC1f: myosin, light polypeptide 1; PRMT: protein arginine N-methyltransferase; sgRNA: single guide RNA; SQSTM1: sequestosome 1; SOL: soleus; TA:tibialis anterior; TRIM63/MURF-1: tripartite motif-containing 63; YY1: YY1 transcription factor
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생명과학대학 (생명과학부)
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