Abstract Skeletal muscle atrophy is a common complication following immobilization, nerve injury, and musculoskeletal trauma such as tendon injuries. Older patients are especially susceptible and are far less able to cope with the consequences. In spite of its obvious clinical importance, the pathobiology of muscle atrophy remains poorly understood, and no pharmacologic treatments are currently available. In our preliminary study, we have observed rapid and predictable atrophy of the gastrocnemius muscle after Achilles tendon transection, which is associated with up-regulation of MMP-2, a key enzyme responsible for ECM degradation and remodeling. We discovered that MMP-2 null mice undergo markedly less muscle atrophy and matrix degradation compared to wild type controls after tendon transection. Furthermore, we found that loss of MMP-2 has a much greater impact on muscle atrophy in older mice than it does in younger mice. Interestingly, our pilot experiments also show that MMP-2 is upregulated during muscle atrophy resulting from nerve injury, but not during muscle atrophy resulting from limb suspension. This data suggests that the significance of MMP-2 activity in pathobiology of muscle atrophy may vary between different muscle atrophy models. Thus, in our proposed study, we will comprehensively analyze the functional role of MMP-2 on key measures of muscle atrophy in vivo using three mouse models with particular relevance to military and VA populations-muscle atrophy following tendon injury, nerve injury and limb unloading. We will then use a series of transgenic mice to define the regulatory networks responsible for increased MMP-2 expression in muscle atrophy. Parallel experiments will be performed using older mice to identify age-dependent changes in the role for MMP-2 in the pathogenesis of muscle atrophy. Finally, we will test the hypothesis that specific inhibitors targeted at MMP-2 can decrease or prevent muscle atrophy, at least in models where significant activity of MMP-2 is observed. We believe novel information gained from this study will greatly help us in understanding the relationship between MMP-2 and muscle atrophy and may further lead to new therapeutic approaches designed to treat skeletal muscle atrophy.