INTRODUCTION: Lower-limb disuse from immobilization results in a decrease in muscle strength, volume, and function. However, muscle atrophy from disuse does not entirely account for the observed strength and functional declines. Additionally, prior engagement in resistance training (RT) has been linked to the preservation of muscular strength and neuromuscular function. Therefore, the purpose of this study was to assess the influence of a single-leg immobilization protocol, followed by structured RT rehabilitation protocol, on muscle strength, volume, and neural activation in healthy young adults with and without previous strength training experience. Methods: Participants (10 Trained (T): 8 men, 2 women; 11 Untrained (UT): 8 men, 3 women) underwent 2-weeks of left-knee immobilization at 90° knee-flexion with a hinged immobilizer knee-brace. Participants were given a pair of axillary crutches for ambulation during this time. Following immobilization, all participants underwent an 8-week structured RT rehabilitation protocol. Participants visited the laboratory for three testing sessions (baseline test on Day 0; post-immobilization at the end of week 2; and post-RT rehab at the end of week 10). Maximal knee extensor isometric strength at 45°was quantified using an isokinetic dynamometer (Biodex). Voluntary muscle activation was quantified as the root mean square (RMS) of the interference electromyography (EMG) signals derived from two indwelling fine-wire electrodes in the vastus-lateralis muscle. Additionally, a continuous wavelet transform (CWT) was performed on the EMG to determine amplitude versus frequency characteristics of the signals and how this amplitude varied with time in the 13-30 (beta) and 30-60 (piper) Hz bands. Mid-thigh muscle cross-sectional area (mCSA) and density were also quantified using peripheral quantitative computed tomography (pQCT) during all testing sessions. Results: The T group was significantly stronger (p=0.019), had greater muscle density (p=0.005) and mid-thigh mCSA (p<0.001) across all sessions when compared with the UT group. However, there were no significant time or interaction effects for strength or muscle density losses (p>0.05). While both groups demonstrated increased muscle activation across sessions (RMS: p=0.04; CWT: p=0.021), the T group demonstrated a greater increase in the neural drive from baseline to week 10 when compared with the UT group (RMS: p= 0.002; CWT: p=0.027). CONCLUSION: In younger adults with or without prior strength training experience, we find that losses in knee extensor isometric strength, muscle density, and mid-thigh mCSA are minimal following a 2-week immobilization protocol. However, certain neuromuscular adaptations during immobilization and following weight-training rehabilitation are enhanced to a greater degree in those with prior training, which is seemingly indicative of greater synchrony in descending cortical drive and motor unit recruitment. These latter findings warrant continued investigation using additional innovative methodologies (e.g., fMRI, TMS, etc.) for assessing the mechanisms underlying the effects of prehab protocols on neuromuscular adaptations. PGRF and Nix family foundation scholarship to Marina Meyer. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.