title: Foxk1 promotes cell proliferation and represses myogenic differentiation by regulating Foxo4 and Mef2.
abstract: In response to severe injury, adult skeletal muscle exhibits a remarkable regenerative capacity due to a resident muscle stem/progenitor cell population. While a number of factors are expressed in the muscle progenitor cell (MPC) population, the molecular networks that govern this cell population remain an area of active investigation. In this study, utilizing knockdown techniques and overexpression of Foxk1 in the myogenic lineage, we observed dysregulation of Foxo and Mef2 downstream targets. Utilizing an array of technologies, we establish that Foxk1 represses the transcriptional activity of Foxo4 and Mef2 and physically interacts with Foxo4 and Mef2, thus promoting MPC proliferation and antagonizing the myogenic lineage differentiation program, respectively. Correspondingly, knockdown of Foxk1 in C2C12 myoblasts results in cell cycle arrest, and Foxk1 overexpression in C2C12CAR myoblasts retards muscle differentiation. Collectively, we have established that Foxk1 promotes MPC proliferation by repressing Foxo4 transcriptional activity and inhibits myogenic differentiation by repressing Mef2 activity. These studies enhance our understanding of the transcriptional networks that regulate the MPC population and muscle regeneration.
authors.affiliation: Lillehei Heart Institute, University of Minnesota-Twin Cities, Minneapolis, MN 55455,  USA.
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Shi
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Wallis
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Voelker
authors.forename: Robert W
authors.initials: RW
authors.lastname: Grange
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Mary G
authors.initials: MG
authors.lastname: Garry
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Garry
mesh_terms: D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D011485:Protein Binding; D012038:Regeneration; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; C525394:FoxO4 protein, mouse; C497672:Foxk1 protein, mouse; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; D004247:DNA