Pathological Foundations of Skeletal Muscle After Volumetric Muscle Loss and Targets For Rehabilitation

摘要 骨科四肢创伤是导致长期功能残疾和严重残疾的主要问题。 不同人群的医疗费用。其中一种损伤是体积性肌肉丢失(VML)，这是临床上确定的 作为一种慢性的、不可恢复的骨骼肌组织丢失，导致功能损害。VML是耦合的 临床结果与长期功能障碍、行动能力和体力活动减少、合并症、 而且经常推迟截肢。此外，在临床上发现的一个主要问题是无法对 康复；即使是长期和密集的康复也不能改善功能 减损。康复的基本原则围绕着骨骼肌的可塑性，或称 能够适应感知到的机械或化学提示，以提高其功能能力 效率。我们假设VML损伤后残留肌肉的病理生理限制与 缺乏内源性再生能力，如全身新陈代谢改善。我们相信，对于 VML损伤的患者、剩余肌肉的病理生理变化以及损伤的共病，例如 代谢不灵活，可能和收缩组织的原发丧失一样是个问题。到目前为止，一个 缺乏对损伤的自然后遗症的全面了解，具体地说，缺乏对 损伤后残留的肌肉以及破坏性的病理生理变化如何影响固有特性 肌肉的力量。我们的中心假设是肌肉功能障碍、肌肉纤维和全身代谢 功能不全和神经肌肉缺陷在剩余肌肉中创造了一个敌对的细胞环境， 减轻肌肉的可塑性，削弱再生性康复的有效性。我们提出了三个具体的 目的是解决这些假说：1)建立神经支配减弱的信号机制 VML后剩余肌肉；2)确定剩余肌肉氧化适应的细胞机制 3)测定VML后剩余肌肉对全身代谢的贡献 改善再生性康复。拟议的研究结果将定义细胞机制， 对VML后剩余肌肉有限的适应和再生能力有贡献，我们预计 这些结果可能会改变VML急性和慢性损伤患者的临床护理。 此外，对骨骼肌缺乏再生潜力的基本理解可能是 转化为骨骼肌的其他情况，如肌营养不良症，非营养不良肌病， 和骨质疏松症。

Abstract Orthopaedic extremity trauma is a major problem resulting in both long-term functional disability and substantial medical cost in various populations. One such injury is volumetric muscle loss (VML), which is clinically identified as a chronic and irrecoverable loss of skeletal muscle tissue resulting in functional impairments. VML is coupled with clinical outcomes related to long-term dysfunction, reduced mobility and physical activity, co-morbidities, and often delayed amputation. Additionally, a major problem identified in the clinic is an inability to respond to rehabilitation; even prolonged and intensive rehabilitation has not been able to ameliorate functional impairments. The fundamental principles of rehabilitation revolve around the plasticity of skeletal muscle, or the ability to adapt to perceived mechanical or chemical cues in order to improve its functional capacity and efficiency. We hypothesize that pathophysiologic limitations in the muscle remaining after VML injury relate to lack of endogenous regenerative ability, such as improvements in whole-body metabolism. We believe that for the VML-injured patient, pathophysiologic changes to the remaining muscle and co-morbidities to injury, such as metabolic inflexibility, could be as much of a problem as the primary loss of contractile tissue. To date, a comprehensive understanding of the natural sequela of injury is absent, specifically, an understanding of the muscle remaining after injury and how the devastating pathophysiologic changes impact the inherent properties of muscle. Our central hypothesis is that muscle dysfunction, muscle fiber and whole-body metabolic insufficiency, and neuromuscular deficiency create a hostile cellular environment in the remaining muscle that mitigates muscle plasticity and blunts the effectiveness of regenerative rehabilitation. We propose three specific aims to address these hypotheses: 1) To establish signaling mechanisms of diminished innervation in the remaining muscle after VML; 2) To identify cellular mechanisms of oxidative adaptation in the remaining muscle after VML; and 3) To determine the contribution of the remaining muscle to whole-body metabolism after VML to improve regenerative rehabilitation. The results of the proposed studies will define cellular mechanisms that contribute to the finite adaptive and regenerative capacity of the remaining muscle after VML and we expect these results could transformative to clinical care for VML-injured patients both acutely and chronically. Additionally, fundamental understanding of the lack of regenerative potential in skeletal muscle could be transformative to other conditions of skeletal muscle such as muscular dystrophies, non-dystrophic myopathies, and sarcopenia.