Molecular Signatures of Muscle Rehabilitation

描述（由申请人提供）：废用引起的肌肉萎缩和无力是常见的临床现象，严重影响日常生活活动，是康复的主要挑战。为了最大限度地增强力量而设计的康复计划可能不是最佳的，而且恢复的速度和程度因人而异。我们将在患者队列中识别与康复后肌肉重塑相关的分子（转录）特征。该建议的关键假设是，该研究小组先前发现的四种重塑特征（偏心/损伤、TGFbeta/MAPK、萎缩和有氧调节）的诱导程度与肢体失用后康复期间功能恢复的速度和程度相关。

DESCRIPTION (provided by applicant): Muscle atrophy and weakness secondary to disuse are common clinical phenomena, which can significantly impact activities of daily living and present a major challenge in rehabilitation. Rehabilitation programs designed to maximize strength gains may not be optimal, and the speed and extent of recovery is highly variable between individuals. We will identify the molecular (transcriptional) signatures associated with muscle remodeling in response to rehabilitation in a patient cohort. The key hypothesis of this proposal is that the rate and extent of functional recovery during rehabilitation following limb disuse correlates with the extent of induction of four remodeling signatures eccentric/damage, TGFbeta/MAPK, atrophy and aerobic conditioning) previously identified by this investigative team. 60 patients with a closed malleolus fracture, treated conservatively using a short leg cast for a period of 6 weeks will be recruited. Following cast-immobilization, subjects will be enrolled in a standardized 6-week rehabilitation program (3 sessions/week) focusing on progressive resistance training of the ankle plantar flexor muscles. The phenotypic response (Aim 1) to cast-immobilization and rehabilitation will be assessed in all individuals using isokinetic testing, magnetic resonance imaging and functional assessment tests. Phenotypic measurements will be performed before, during and immediately after the rehabilitation intervention. Ankle plantar flexor muscle size and strength measurements will also be performed on the uninvolved limb (serves as a control) at 6 months post-immobilization. In Aim 2, four longitudinal biopsies will be taken from the medial gastrocnemius of each individual and expression profiled over the entire human genome (U133A/B). The first 30 individuals will be used as the data generation "test set" (years 1-3), and the second 30 individuals as a "validation set" (years 3-5). In Aim 3, we will determine the correlation between the phenotypes defined in Aim 1 (percentage change in size, muscle strength, functional performance), and the "relative induction/repression" of the four remodeling signatures (eccentric/damage, TGFbeta/MAPK, muscle atrophy and aerobic conditioning). The development of effective therapeutic interventions targeting restoration of muscle function necessitates an in-depth understanding of the cellular and molecular mechanisms mediating muscle atrophy and subsequent repair. We anticipate that this study will provide essential feedback for the design and development of effective, individualized, rehabilitation interventions.