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

Seri Choi; Hyeon Ju Jeong; Hyebeen Kim; Dahee Choi; Sung Chun Cho; Je Kyung Seong; Seung Hoi Koo; Jong Sun Kang

doi:10.1080/15548627.2019.1569931

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

Seri Choi, Hyeon Ju Jeong, Hyebeen Kim, Dahee Choi, Sung Chun Cho, Je Kyung Seong, Seung Hoi Koo, Jong Sun Kang

Research output: Contribution to journal › Article › peer-review

60 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	1069-1081
Number of pages	13
Journal	Autophagy
Volume	15
Issue number	6
DOIs	https://doi.org/10.1080/15548627.2019.1569931
Publication status	Published - 2019 Jun 3

Keywords

Arginine methylation
FOXO3
PRMT1
PRMT6
muscle atrophy

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1080/15548627.2019.1569931

Cite this

@article{46ae866f788b4368a6dddac4288b01da,

title = "Skeletal muscle-specific Prmt1 deletion causes muscle atrophy via deregulation of the PRMT6-FOXO3 axis",

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 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.",

keywords = "Arginine methylation, FOXO3, PRMT1, PRMT6, muscle atrophy",

author = "Seri Choi and Jeong, {Hyeon Ju} and Hyebeen Kim and Dahee Choi and Cho, {Sung Chun} and Seong, {Je Kyung} and Koo, {Seung Hoi} and Kang, {Jong Sun}",

note = "Funding Information: This research was supported by the National Research Foundation of Korea Grant funded by the Korean Government (MSIP) (NRF-2016R1A2B2007179, NRF-2017M3A9D8048710 and NRF-2016R1A5A2945889 to J.S.K., and NRF-2018R1A2B3001540, NRF-2015R1A5A1009024 and NRF-2017M3A 9D5A01052447 to S.H.K.). Publisher Copyright: {\textcopyright} 2019, {\textcopyright} 2019 Informa UK Limited, trading as Taylor & Francis Group.",

year = "2019",

month = jun,

day = "3",

doi = "10.1080/15548627.2019.1569931",

language = "English",

volume = "15",

pages = "1069--1081",

journal = "Autophagy",

issn = "1554-8627",

publisher = "Landes Bioscience",

number = "6",

}

TY - JOUR

T1 - Skeletal muscle-specific Prmt1 deletion causes muscle atrophy via deregulation of the PRMT6-FOXO3 axis

AU - Choi, Seri

AU - Jeong, Hyeon Ju

AU - Kim, Hyebeen

AU - Choi, Dahee

AU - Cho, Sung Chun

AU - Seong, Je Kyung

AU - Koo, Seung Hoi

AU - Kang, Jong Sun

N1 - Funding Information: This research was supported by the National Research Foundation of Korea Grant funded by the Korean Government (MSIP) (NRF-2016R1A2B2007179, NRF-2017M3A9D8048710 and NRF-2016R1A5A2945889 to J.S.K., and NRF-2018R1A2B3001540, NRF-2015R1A5A1009024 and NRF-2017M3A 9D5A01052447 to S.H.K.). Publisher Copyright: © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2019/6/3

Y1 - 2019/6/3

N2 - 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.

AB - 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.

KW - Arginine methylation

KW - FOXO3

KW - PRMT1

KW - PRMT6

KW - muscle atrophy

UR - http://www.scopus.com/inward/record.url?scp=85061028761&partnerID=8YFLogxK

U2 - 10.1080/15548627.2019.1569931

DO - 10.1080/15548627.2019.1569931

M3 - Article

C2 - 30653406

AN - SCOPUS:85061028761

SN - 1554-8627

VL - 15

SP - 1069

EP - 1081

JO - Autophagy

JF - Autophagy

IS - 6

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this