Bone and skeletal muscle are closely linked across development, growth and aging. However, the functional interactions between bone and muscle have been poorly investigated. It is clear that a better understanding of the bone-muscle cross talks will be key to challenge numerous diseases and disorders of the musculoskeletal system. Musculoskeletal disorders affect 1 in 7 people (over 70 million in Europe). These disorders can cause long-term disabilities and have a considerable impact on public health. The goal of this proposal is to elucidate the cross talks between bone and muscle tissues at the cellular and molecular levels, in the context of tissue regeneration after combined trauma to muscle and bone. Under severe trauma, musculoskeletal injuries often cause damage of both skeletal and muscle tissues. Yet most experimental approaches address the repair of bone on one hand and the repair of muscle on the other hand. Although bone and skeletal muscle injuries trigger very efficient regenerative processes, through the activation of endogenous stem cell populations and release of growth factors within theses tissues, there are many clinical situations where bone and/or muscle regeneration need to be enhanced. We hypothesize that bidirectional interactions between skeletal muscle and adjacent bone, and most specifically the periosteum, are required during musculoskeletal regeneration, via contribution of stem cell populations and regulatory molecular systems from bone and muscle. Our preliminary data strongly suggest that bone-muscle bidirectional interactions exist at the cellular and/or molecular levels. In particular, we showed that muscle is essential to induce proper activation of skeletal stem cells within periosteum, a key cellular contributor to bone repair and a central tissue involved in these bone-muscle cross talks, as it lies at the interface between bone and muscle. We propose 3 aims, which will explore complementarily aspects of the role of bone-muscle cross talks during musculoskeletal regeneration at the tissue, cellular and molecular levels. We will define the stem cell contribution of periosteum and muscle to musculoskeletal regeneration, the role of the BMP pathways in mediating these molecular interactions and finally, we will aim to identify new mediators in these molecular cross talks between bone and muscle. We will use our well-established mouse models of musculoskeletal regeneration and various genetic tools to define the role of skeletal stem cells and muscle stem cells (i.e. satellite cells) during tissue regeneration. This project will combine the complementary expertise of the two partners in muscle and bone repair. By better understanding the cellular and molecular bases of musculoskeletal regeneration and the mechanisms of endogenous stem cell recruitment from muscle and bone following injury, we will be able to propose new drug-based and cell-based strategies to promote the regeneration of these tissues.