BMP signalling permits population expansion by preventing premature myogenic differentiation in muscle satellite cells

Peter Zammit (1) , Yusuke Ono (1) , Frederico Calbaheu (1) , Helge Amthor (1) , Jennifer Morgan (1) , Takenobu Katagiri (1)

1 Randall Division

Satellite cells are the resident stem cells of adult skeletal muscle, supplying myonuclei for homeostasis, hypertrophy and repair. Here, we have examined the role of Bone morphogenetic protein (BMP) signalling in regulating satellite cell function. Activated satellite cells expressed BMP receptor-1A (BMPR-1A) and contained phosphorylated Smad proteins, indicating that BMP signalling is operating during proliferation. Indeed, exogenous BMP4 stimulated satellite cell division and inhibited myogenic differentiation. Conversely, interfering with the interactions between BMPs and their receptors by the addition of either the BMP antagonist Noggin or soluble BMPR-1A fragments, induced precocious differentiation. Similarly, blockade of BMP signalling by siRNA-mediated knockdown of BMPR-1A, or disruption of the intracellular pathway by either Smad5 or Smad4 knockdown or inhibition of Smad1/5/8 phosphorylation with Dorsomorphin, also caused premature differentiation. BMP signalling acted to inhibit the up-regulation of genes associated with differentiation, in part, through regulating Id1. As satellite cells differentiated, Noggin levels increased to antagonise BMP signalling, since Noggin knockdown enhanced proliferation and impeded differentiation. Finally, interference of normal BMP signalling after muscle damage in vivo resulted in smaller regenerated myofibres. In conclusion, BMP signalling operates during routine satellite cell function to help coordinate the balance between proliferation and differentiation, before Noggin is activated to antagonise BMPs and facilitate terminal differentiation.

Mots clés: Satellite cell; BMP signaling; myogenic differentiation; Noggin; muscle regeneration

Peter Zammit, Yusuke Ono, Frederico Calbaheu, Helge Amthor, Jennifer Morgan, et al.. BMP signalling permits population expansion by preventing premature myogenic differentiation in muscle satellite cells. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.95⟩. ⟨hal-00563514⟩