Myostatin imposes reversible quiescence on embryonic muscle precursors

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Abstract
We have previously shown that Myostatin, a member of the transforming growth factor beta (TFG-β) family of signalling molecules, is expressed in developing muscle, and that treatment with recombinant Myostatin inhibited the expression of key myogenic transcription factors during chick embryogenesis. In this study, we followed the fate of muscle precursors after exposure to Myostatin. We report that in contrast to the down-regulation in expression of Pax-3, Myf-5, MyoD, and Myogenin, expression of Pax-7 was maintained. However, Myostatin completely inhibited cell division in the Pax-7-expressing cells. The inhibitory effect of Myostatin was reversible, as upon withdrawal myogenic cells re-initiated cell proliferation as well as expression of Pax-3 and MyoD. These results led us to investigate the temporal and spatial distribution of quiescent muscle precursors during development. To this end, we analysed distribution and mitotic behaviour of Pax-7-expressing cells during muscle development. Our studies revealed two populations of Pax-7-expressing cells, one that proliferated and incorporated BrdU, whilst the other did not. At early developmental stages, a high proportion of Pax-7-expressing cells proliferated, but there was a significant number of non-dividing Pax-7-expressing cells intermingled with differentiated muscle. Proliferating precursors became less frequent as development proceeded and at late fetal stages all Pax-7-expressing cells were mitotically quiescent. We suggest that Myostatin is an important signalling molecule responsible for imposing quiescence upon myogenic precursors during embryonic and foetal development. © 2006 Wiley-Liss, Inc. Developmental Dynamics 235:672–680, 2006.