Résumé :
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Bone Morphogenetic Proteins (BMPs), a subfamily of signaling molecules of the TGF-beta family, and their antagonist Noggin regulate embryonic and fetal muscle growth. Moreover, a recent in-vitro study demonstrated that the signaling system BMP/Noggin also regulates the balance between proliferation, differentiation and self-renewal of the resident stem cells of postnatal skeletal muscle, termed satellite cells (SCs). Here we hypothesize that BMP signaling regulates muscle stem cell dependent growth of postnatal skeletal muscle and regeneration of adult skeletal muscle following myoinjury and in the Mdx mouse model of Duchenne muscular dystrophy.We abrogated BMP signaling in postnatal skeletal muscle of mice using an AAV2/1-Noggin expression vector. Intramuscular injection of AAV-Noggin at postnatal day 3 resulted in a severe growth retardation of skeletal muscle. AAV-Noggin strongly reduced the number of muscle SCs, and myofibres were much smaller and contained a decreased number of myonuclei. This suggests that in absence of BMP signaling, muscle SCs failed to generate sufficient progenitors to enable continuous myofibre growth. Similarly, treatment with AAV-Noggin impaired myofibre regeneration following myoinjury, and the number of Pax7 expressing SCs in regenerating muscle was decreased. Finally, we can show that abrogation of BMP signaling resulted in a loss of quiescent muscle SCs in non-injured adult skeletal muscle and in strong myofibre atrophy.We conclude that BMP signaling is required for myofibre growth and regeneration by stimulating the generation of muscle satellite cell-derived myoblasts. Furthermore, BMP signaling is required to maintain the reservoir of quiescent SCs in adult non-injured muscle. Furthermore, hypertrophic muscle growth and maintenance of adult muscle depend on BMP signaling. We suggest that modulation of BMP signaling could provide a novel therapeutical approach to regenerate skeletal muscle following muscle wasting.
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