Project Abstract Each year in the United States, a quarter million individuals will severely injure their anterior cruciate ligament (ACL), and half will develop radiographic signs of knee osteoarthritis (OA) within ten years. Unfortunately, evidence-based interventions to prevent post-traumatic knee OA do not yet exist. Changes in joint structure and function that are linked to radiographic knee OA occur quickly after ACL injury, particularly 1) alterations in articular cartilage matrix organization on quantitative magnetic resonance imaging (MRI) within two months after ACL reconstruction, 2) abnormal joint unloading early after ACL injury and six months after ACL reconstruction, and 3) self-reported poor knee function before ACL reconstruction. Insufficient physical activity levels play a role in OA in older adults, but their influence in progression to post-traumatic OA is unknown, particularly in combination with joint loading. Understanding these early changes and relationships between physical activity levels and movement patterns with later joint outcomes (articular cartilage breakdown, knee function) is critical for future development of interventions to hinder progression to OA. The purpose of this study is to identify markers that predict the earliest signs of poor joint outcomes after ACL injury. We will measure daily physical activity through accelerometry (step counts) and biomechanical function (peak knee moments during loading phase of gait) in participants within one month of ACL injury and again at two, four, and six months after ACL reconstruction. Participants will complete MRI testing at baseline and six months after ACL reconstruction to determine changes in the articular cartilage microstructure (measured by T2 relaxation time). Knee function will be measured by the Knee injury and Osteoarthritis Outcome Score (KOOS) at six months after ACL reconstruction. In Aim 1, we will determine how physical activity levels and biomechanical function before and after ACL reconstruction relate to changes in T2 relaxation time at 6 months after ACL reconstruction. Cumulative joint loading (product of mean steps per day and knee flexion moment) will be tested against individual physical activity and biomechanical factors to determine the strongest joint loading determinant of T2 relaxation time. In Aim 2, we will identify levels of daily physical activity that predict poor post-operative knee function on the KOOS. This work will define movement biomarkers that predict early changes in cartilage microstructure (Aim 1) and post-operative knee joint function (Aim 2) after ACL injury. Successful completion of this study will result in identification of an initial target or range of healthy knee joint loading levels after ACL injury. Our findings will provide a foundation to test the efficacy of different regimens aimed at optimizing joint loading to reduce degenerative changes in articular cartilage following ACL injury. We predict that these...