Abstract Chronic musculoskeletal pain is a very common and frequently disabling condition that affects up to 50% of the adult population worldwide, having a huge impact on quality of life and economic burden, loses related to medical expenses, lower labor productivity and increased compensation claims. Unfortunately, our lack of understanding of the mechanisms underlying this condition has precluded the development of rationale, safe and effective therapies. While some people display resilience to chronic musculoskeletal pain, research has only focused on the psychological aspects involved in such resilience. However, growing evidence suggests that, in addition to psychological factors, a physical component is critical to achieve resilience to chronic pain and that failure to display adequate reparative and/or regenerative responses is associated with persistent pain. The phenomenon of repeated bout effect (RBE) is a common and natural example of the involvement of an endogenous reparative response (i.e., physical resilience) to muscle injury and persistent pain. Initial exposure to strenuous muscle activity produces significant pain, loss of force and tissue damage, which over time resolves without any external intervention. Re-exposure to the same activity, will however, produce much less pain, dysfunction and tissue damage, suggesting that physical resilience is enhanced by the muscle activity. Although recent research has underlined the importance of immune, endocrine and neural responses in muscle repair and regeneration, whether they also contribute to recovery from persistent musculoskeletal pain is unknown. Furthermore, whether exposure to stress or repetitive ergonomic tasks interferes with physical resilience, leading to chronic musculoskeletal pain, remains unknown. We plan to combine our expertise in several experimental approaches and our new preclinical model of RBE to study physical resilience, to achieve the three major goals of this proposal: (1) elucidate the role of muscle activity in physical resilience, with emphasis on mechanisms of ergonomic injury-induced chronic muscle pain; (2) evaluate the interaction between stress and physical resilience on chronic musculoskeletal pain, especially in regard to the role of early-life interventions on physical resilience and muscle nociceptor hyperexcitability; and, (3) assess the effect of physical resilience on neuropathic muscle pain, with emphasis on cellular and molecular mechanisms of muscle nociceptor dysfunction. !