Prehabilitative Exercise Mitigates Immobilization-Induced Atrophy Through Muscle Reserve Rather Than Resistance to Disuse: The PRE-EX Randomized Controlled Trial

Periods of limb immobilization are common in clinical care and lead to rapid losses of muscle mass and strength. We therefore examined whether prehabilitative exercise improves outcomes after disuse by increasing pre-immobilization muscle reserve or by attenuating the biological response to immobilization. Here, we report the primary and muscle-focused secondary outcomes of the PRE-EX (PREhabilitative EXercise) randomized controlled trial (ClinicalTrials.gov: NCT06205784). Fifty-four healthy younger and older women completed four weeks of supervised resistance exercise or no training before eight days of unilateral limb immobilization, followed by four weeks of rehabilitation. From baseline to pre-immobilization, prehabilitation increased quadriceps cross-sectional area (CSA) by 6.7%, maximal voluntary contraction (MVC) by 15.2%, and muscle fiber CSA by 17.7%. Immobilization subsequently reduced quadriceps CSA by 3.2% over 5 days and MVC by ~20%, with similar relative losses in the Prehab and No-train groups. Consequently, quadriceps CSA, the studys primary outcome, remained greater in Prehab than in No-train after immobilization and following rehabilitation, while MVC was greater following rehabilitation. Prehabilitation did not preserve markers of neuromuscular innervation or produce a detectable post-immobilization transcriptomic signature. Instead, immobilization elicited an extensive transcriptional response comprising more than 7000 differentially expressed genes, characterized by activation of inflammatory, proteolytic, stress, and denervation-associated programs together with suppression of mitochondrial and muscle-structural pathways. Network analysis further linked these coordinated molecular programs to disuse-related changes in muscle size, strength, and morphology. The effects of prehabilitation and the subsequent response to immobilization were similar in younger and older women. These findings demonstrate that short-term prehabilitative exercise mitigates the consequences of limb immobilization by establishing greater muscle and strength reserve before disuse, rather than by attenuating the physiological or molecular response to immobilization.