Sarafraz Ahmad1, Arif Tasleem Jan1, Mohammad Hassan Baig1, Eun Ju Lee1, Inho Choi2. 1. Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea. 2. Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address: inhochoi@ynu.ac.kr.
Abstract
AIM: Skeletal muscle development involves interactions between intracellular and extracellular factors that act in concert to regulate the myogenic process. Matrix gla protein (MGP), a well-known inhibitor of calcification in soft tissues, has been reported to be highly up-regulated during myogenesis. Our interest in the regulation of muscle satellite cells (MSCs) by extracellular matrix (ECM) led us to investigate the effects of MGP during the progression of myogenesis. METHODOLOGY: Participation of MGP in the myogenic process was investigated in vitro using C2C12 cells, and knockdown of its gene was performed to determine its effects on the expression of myogenic regulatory factors (MRFs) and other ECM genes. In addition, interactions between MGP, Fibromodulin (FMOD), and Myostatin (MSTN) were investigated by conducting co-immunoprecipitation and in silico studies. KEY FINDINGS: Matrix gla protein knockdown (MGPkd) shows pronounced effects during myogenesis as evidenced by the down regulation of myogenic marker (MYOG and MYOD), and ECM (COL1α1 and FMOD) genes. Down-regulation of MSTN expression in MGPkd cells suggests its role in coordinating the regulation of MSTN expression. Having strong affinity for ACVRIIB receptor, in silico data confirms MGP interference in the interaction of MSTN with ACVRIIB. These findings show MGP inhibits MSTN functionally by disrupting its binding to receptor. SIGNIFICANCE: The present study provides insights of an ECM protein that participates in the regulation of the myogenic program by inhibiting the activity of the myogenic negative regulator MSTN, which suggests that MGP might be used for designing novel inhibitors that can promote muscle regeneration or treat muscle atrophy.
AIM: Skeletal muscle development involves interactions between intracellular and extracellular factors that act in concert to regulate the myogenic process. Matrix gla protein (MGP), a well-known inhibitor of calcification in soft tissues, has been reported to be highly up-regulated during myogenesis. Our interest in the regulation of muscle satellite cells (MSCs) by extracellular matrix (ECM) led us to investigate the effects of MGP during the progression of myogenesis. METHODOLOGY: Participation of MGP in the myogenic process was investigated in vitro using C2C12 cells, and knockdown of its gene was performed to determine its effects on the expression of myogenic regulatory factors (MRFs) and other ECM genes. In addition, interactions between MGP, Fibromodulin (FMOD), and Myostatin (MSTN) were investigated by conducting co-immunoprecipitation and in silico studies. KEY FINDINGS:Matrix gla protein knockdown (MGPkd) shows pronounced effects during myogenesis as evidenced by the down regulation of myogenic marker (MYOG and MYOD), and ECM (COL1α1 and FMOD) genes. Down-regulation of MSTN expression in MGPkd cells suggests its role in coordinating the regulation of MSTN expression. Having strong affinity for ACVRIIB receptor, in silico data confirms MGP interference in the interaction of MSTN with ACVRIIB. These findings show MGP inhibits MSTN functionally by disrupting its binding to receptor. SIGNIFICANCE: The present study provides insights of an ECM protein that participates in the regulation of the myogenic program by inhibiting the activity of the myogenic negative regulator MSTN, which suggests that MGP might be used for designing novel inhibitors that can promote muscle regeneration or treat muscle atrophy.
Authors: Obiajulu Agha; Agustin Diaz; Michael Davies; Hubert T Kim; Xuhui Liu; Brian T Feeley Journal: Ann N Y Acad Sci Date: 2020-07-29 Impact factor: 5.691
Authors: Garan Jones; Katerina Trajanoska; Adam J Santanasto; Najada Stringa; Chia-Ling Kuo; Janice L Atkins; Joshua R Lewis; ThuyVy Duong; Shengjun Hong; Mary L Biggs; Jian'an Luan; Chloe Sarnowski; Kathryn L Lunetta; Toshiko Tanaka; Mary K Wojczynski; Ryan Cvejkus; Maria Nethander; Sahar Ghasemi; Jingyun Yang; M Carola Zillikens; Stefan Walter; Kamil Sicinski; Erika Kague; Cheryl L Ackert-Bicknell; Dan E Arking; B Gwen Windham; Eric Boerwinkle; Megan L Grove; Misa Graff; Dominik Spira; Ilja Demuth; Nathalie van der Velde; Lisette C P G M de Groot; Bruce M Psaty; Michelle C Odden; Alison E Fohner; Claudia Langenberg; Nicholas J Wareham; Stefania Bandinelli; Natasja M van Schoor; Martijn Huisman; Qihua Tan; Joseph Zmuda; Dan Mellström; Magnus Karlsson; David A Bennett; Aron S Buchman; Philip L De Jager; Andre G Uitterlinden; Uwe Völker; Thomas Kocher; Alexander Teumer; Leocadio Rodriguéz-Mañas; Francisco J García; José A Carnicero; Pamela Herd; Lars Bertram; Claes Ohlsson; Joanne M Murabito; David Melzer; George A Kuchel; Luigi Ferrucci; David Karasik; Fernando Rivadeneira; Douglas P Kiel; Luke C Pilling Journal: Nat Commun Date: 2021-01-28 Impact factor: 14.919