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Skeletal muscle-specific Prmt1 deletion causes muscle atrophy via deregulation of the PRMT6-FOXO3 axis
Open accessAbstract
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 A1; 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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“Among the different post-translational modifications of FoxOs, it has been recently shown that arginine 188 and 249 methylation by the arginine methyltransferase PRMT6 enhances the catabolic action of FoxO379.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [79]
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Metadata
- Authors
- Choi, S., Jeong, H.-J., Kim, H., Choi, D., Cho, S.-C., Seong, J. K., Koo, S.-H., & Kang, J.-S.
- Affiliations
- Korea University (KR)
- Sungkyunkwan University (KR)
- Samsung (South Korea) (KR)
- Seoul National University (KR)
- Corresponding author
- Koo, Seung-Hoi
- Kang, Jong-Sun
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2019-02-05
- Volume
- 15
- Issue
- 6
- Pages
- 1069-1081
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC6526864
- OpenAlex
- W2908751660
- Cited by
- 132
- References
- 61
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 23 · 2023: 25 · 2022: 24 · 2021: 14 · 2020: 10 · 2019: 7
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Research Foundation of Korea (NRF-2016R1A2B2007179)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Keywords
- PRMT1, PRMT6, FOXO3, skeletal muscle atrophy, protein arginine methyltransferase, ubiquitin ligase, atrogin-1, protein degradation, muscle homeostasis, arginine methylation, LC3-II, muscle regeneration, muscle metabolism
- MeSH terms
- Tripartite Motif Proteins, Forkhead Box Protein O3, Proto-Oncogene Mas, Histone Deacetylase 3, Animals, Autophagy, Histone Deacetylases, Humans, Methylation, Microtubule-Associated Proteins, Muscle Proteins, Muscular Atrophy, Phosphorylation, Protein-Arginine N-Methyltransferases, Signal Transduction, Mice, Knockout, Muscle, Skeletal, Ubiquitin-Protein Ligases, YY1 Transcription Factor, Mice, Histone Deacetylase 2, HEK293 Cells
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