Acute and chronic skeletal muscle pain and weakness are among the most common ailments in a general medical practice. While treating muscle weakness and pain with pharmaceutical drugs and traditional exercise regimens has met with some success, large numbers of people have turned to alternative approaches including myofacial release, massage, acupuncture, and yoga. According to the American Massage Therapy Association (AMTA, http://www.amtamassage.org) the benefits of massage on muscle include; relief of muscle tension and stiffness, faster healing of strained muscles and sprained ligaments, reduced muscle pain, swelling, and spasm, greater range of motion, and even enhanced athletic performance. Although at this time many claims are made about massage, there are only a few studies to support its use. Moreover, the biological mechanism(s) by which massage works are largely unknown. To this end, we have employed our well-established in vivo rabbit model of eccentric exercise- induced muscle inflammation and weakness that closely mimics muscle injuries in athletes to examine the efficacy of massage therapies. Pilot studies have shown that four sessions of daily massage (using a self-designed and fabricated device capable of producing repeatable loading) can improve recovery of muscle function up to 120% over than the control while at the same time reducing tissue inflammation. Our overall hypothesis is that biomechanical signals generated during massage therapies at the correct magnitude, duration, and frequency are, (i) potent anti- inflammatory signals that inhibit muscle inflammation by suppressing expression of proinflammatory mediators, and (ii) effective signals that augment muscle regeneration and repair by upregulating expression of genes essential for muscle cell proliferation and differentiation. Three aims will be investigated utilizing state of the art technologies and analytical methods to determine an optimal magnitude, duration, and frequency of massage to restore muscle function (peak isometric torque) while investigating the effects of this combination on the host inflammatory and regenerative and reparative responses. This multidisciplinary effort will hopefully provide a strong rationale for future mechanistic studies and eventually clinical trials investigating the optimal indications and strategies for massage therapies to restore skeletal muscle dysfunction and improve overall human health. PUBLIC HEALTH RELEVANCE: Although the effectiveness of massage for overcoming muscle weakness following exercise is limited to a few high quality studies, Americans make more than 160 million visits annually to seek relief of musculoskeletal weakness and pain by manipulative or body-based practices. This basic science research is aimed at understanding the mechanisms of action of massage therapies to understand the basis of their effectiveness and to develop innovative strategies to maximize their clinical effectiveness.