한빛사 논문
Seri Choia,*, Hyeon-Ju Jeongb,*, Hyebeen Kimb, Dahee Choia, Sung-Chun Chod, Je Kyung Seonge, Seung-Hoi Kooa,#, Jong-Sun Kangb,c,#
aDivision of Life Sciences, Korea University, Seoul, South Korea, bDepartment of Molecular Cell Biology, Single Cell Network Research Center, Sungkyunkwan University School of Medicine, cSamsung Biomedical Research Institute, Samsung Medical Center, Seoul, dWell Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics Co. Ltd, Suwon, Gyeonggido, South Korea, eKorea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea
*These authors contributed equally.
# Corresponding authors:
Jong-Sun Kang, Department of Molecular Cell Biology, Sungkyunkwan University School of
Medicine, 2066, Seobu-Ro, Jangan-gu, Suwon, Gyunggi-do, Korea 440-746
Seung-Hoi Koo, Division of Life Sciences, Korea University, Seoul, Korea
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 LC3B, 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.
Keywords: Arginine methylation, FOXO3, muscle atrophy, PRMT1, PRMT6
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