Molecular Signatures of Muscle Rehabilitation

描述（由申请人提供）：废用性肌肉萎缩和无力是常见的临床现象，可显著影响日常生活活动，并对康复提出重大挑战。旨在最大限度地增加力量的康复计划可能不是最佳的，恢复的速度和程度在个体之间存在很大差异。我们将确定与肌肉重塑相关的分子（转录）签名，以响应患者队列中的康复。该建议的关键假设是，肢体废用后康复期间功能恢复的速率和程度与本研究小组先前确定的四种重塑特征（偏心/损伤、TGF β/MAPK、萎缩和有氧条件反射）的诱导程度相关。 将招募60例闭合性踝关节骨折患者，使用短腿石膏保守治疗6周。石膏固定后，受试者将参加为期6周的标准化康复计划（3次/周），重点是踝跖屈肌的渐进式阻力训练。将使用等速测试、磁共振成像和功能评估测试评估所有个体对石膏固定和康复的表型反应（目标1）。将在康复干预之前、期间和之后立即进行表型测量。在固定后6个月，还将对未受累肢体（作为对照）进行踝跖屈肌尺寸和强度测量。 在目标2中，将从每个个体的内侧腓肠肌获取四个纵向活检，并在整个人类基因组（U133 A/B）上进行表达谱分析。前30个个体将用作数据生成"测试集"（第1 - 3年），后30个个体将用作"验证集"（第3 - 5年）。在目标3中，我们将确定目标1中定义的表型（大小、肌肉力量、功能表现的百分比变化）与四种重塑特征（偏心/损伤、TGF β/MAPK、肌肉萎缩和有氧条件）的"相对诱导/抑制"之间的相关性。 针对肌肉功能恢复的有效治疗干预措施的开发需要深入了解介导肌肉萎缩和随后修复的细胞和分子机制。我们预计，这项研究将提供必要的反馈，设计和开发有效的，个性化的，康复干预措施。

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.