Fibromodulin: A master regulator of myostatin controlling progression of satellite cells through a myogenic program

Abstract

Differentiation of muscle satellite cells (MSCs) involves interaction of the proteins present in the extracellular matrix (ECM) with MSCs to regulate their activity, and therefore phenotype. Herein, we report fibromodulin( FMOD), amember of theproteoglycanfamilyparticipatinginthe assemblyofECM, asanovel regulatorof myostatin (MSTN) duringmyoblast differentiation. In addition to having a pronounced effect on the expression of myogenic marker genes [myogenin (MYOG) and myosin light chain 2 (MYL2)], FMOD was found to maintain the transcriptional activity of MSTN.Moreover, coimmunoprecipitation and in silico studies performed to investigate the interaction of FMODhelpedconfirmthat it antagonizesMSTNfunctionbydistorting its folding andpreventing its binding to activin receptor type IIB. Furthermore, in vivo studies revealed that FMOD plays an active role in healing by increasing satellite cell recruitment to sites of injury. Together, these findings disclose a hitherto unrecognized regulatory role for FMOD in MSCs and highlight new mechanisms whereby FMOD circumvents the inhibitory effects ofMSTNandtriggersmyoblastdifferentiation.These findings offer abasis for the design ofnovel MSTNinhibitors thatpromotemuscle regeneration after injury or for the development ofpharmaceutical agents for the treatment of differentmuscle atrophies.-Lee,E. J., Jan,A.T.,Baig,M.H.,Ashraf, J.M.,Nahm, S.-S., Kim, Y.-W., Park, S.-Y.,Choi, I. Fibromodulin: amaster regulator ofmyostatin controlling progression of satellite cells through a myogenic program.