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

摘要 骨科肢体创伤是一个主要问题，导致长期的功能障碍和大量的 不同人群的医疗费用。一种这样的损伤是体积肌肉损失（VML），其在临床上被鉴定为 作为导致功能损伤的骨骼肌组织的慢性和不可恢复的损失。VML耦合 临床结局与长期功能障碍、活动性和体力活动减少、合并症 并且常常延迟截肢。此外，在诊所中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无法改善功能 损伤康复的基本原则围绕着骨骼肌的可塑性，或 能够适应感知的机械或化学线索，以提高其功能能力， 效率我们假设VML损伤后肌肉的病理生理局限性与以下因素有关： 缺乏内源性再生能力，如改善全身代谢。我们认为对于 VML损伤患者，剩余肌肉的病理生理变化和损伤的合并症，如 代谢的不稳定性，可能是一个问题，因为主要损失的收缩组织。迄今为止， 对损伤的自然后遗症缺乏全面的了解，具体来说， 肌肉损伤后的剩余以及破坏性的病理生理变化如何影响固有特性 肌肉。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的肌肉中创造了不利的细胞环境， 减轻肌肉的可塑性和钝化再生康复的有效性。我们提出三个具体的 目的是解决这些假设：1）建立减少神经支配的信号机制， VML后剩余肌肉; 2）确定剩余肌肉中氧化适应的细胞机制 3）确定VML后剩余肌肉对全身代谢的贡献 以改善再生康复。拟议研究的结果将定义细胞机制， 有助于VML后剩余肌肉的有限适应和再生能力，我们预计 这些结果可以改变急性和慢性VML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 转化为骨骼肌的其它病症，例如肌营养不良，非营养不良性肌病， 和肌肉减少症。

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.