Molecular Signatures of Muscle Rehabilitation

描述(由申请人提供)：肌肉萎缩和继发于停用的无力是常见的临床现象，可显著影响日常生活能力，并对康复构成重大挑战。旨在最大限度地增加力量的康复计划可能并不是最佳的，恢复的速度和程度因个人而异。我们将在患者队列中确定与肌肉重塑相关的分子(转录)信号，以响应康复。这一建议的关键假设是，肢体停用后康复期间功能恢复的速度和程度与该研究小组先前确定的四个重塑信号(偏心/损伤、TGFβ/MAPK、萎缩和有氧条件作用)的诱导程度相关。 60例闭合性踝关节骨折患者，采用短腿石膏保守治疗，为期6周。在石膏固定后，受试者将参加为期6周的标准化康复计划(每周3次)，重点是脚踝足底屈肌的渐进性阻力训练。将使用等速测试、磁共振成像和功能评估测试来评估所有个体对石膏固定和康复的表型反应(目标1)。表型测量将在康复干预之前、期间和之后立即进行。在制动后6个月，还将对健侧肢体(作为对照)进行踝足屈肌大小和力量的测量。在目标2中，将从每个个体的腓肠肌内侧进行四次纵向活组织检查，并对整个人类基因组进行表达谱分析(U133A/B)。前30个人将被用作数据生成“测试集”(1-3岁)，第二个30个人将被用作“验证集”(3-5岁)。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、功能表现的变化百分比)和四个重塑信号(偏心/损伤、TGFbeta/MAPK、肌肉萎缩和有氧条件作用)的“相对诱导/抑制”之间的相关性。 发展以恢复肌肉功能为目标的有效治疗干预措施，需要深入了解肌肉萎缩和随后修复的细胞和分子机制。我们预计，这项研究将为设计和开发有效的、个性化的康复干预措施提供必要的反馈。

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.