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

体积肌丢失后骨骼肌的病理学基础和康复目标

基本信息

批准号：
10364333
负责人：
Jarrod A Call
金额：
$ 48.6万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364333
关键词：
Activities of Daily Living Acute Address Amputation Axotomy Biomedical Technology Bypass Chemicals Chronic Clinic Clinical Coupled Cues Denervation Effectiveness Environment Exercise Failure Fatty acid glycerol esters Foundations Functional disorder Guidelines Impairment Individual Injury Knowledge Mechanics Medical Care Costs Metabolic Metabolic syndrome Metabolism Mitochondria Modality Modeling Motor Motor Neurons Movement Muscle Muscle Fibers Muscle function Muscular Dystrophies Myopathy Natural regeneration Neuromuscular Junction Orthopedics Outcome Passive Range of Motion function Pathologic Pathology Patients Physical Medicine Physical activity Physiological Physiology Population Property Publishing Recovery of Function Regenerative Medicine Regenerative capacity Rehabilitation Outcome Rehabilitation therapy Research Signal Pathway Signal Transduction Skeletal Muscle Source Technology Testing Tissues Work clinical care comorbidity daily functioning evidence base exercise training functional disability functional improvement functional outcomes functional restoration improved injured limb injury mitochondrial dysfunction muscle grafts muscle physiology nerve supply neuromuscular patient population presynaptic recruit regeneration potential regenerative regenerative rehabilitation rehabilitation strategy repaired response sarcopenia skeletal muscle plasticity skeletal muscle wasting soft tissue standard of care treatment guidelines two photon microscopy volumetric muscle loss

项目摘要

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.

抽象的骨科肢体创伤是导致长期功能残疾和严重伤害的一个主要问题。不同人群的医疗费用。其中一种损伤是体积肌肉损失（VML），这是临床上发现的作为骨骼肌组织的慢性且不可恢复的损失，导致功能障碍。 VML耦合与长期功能障碍、活动能力和体力活动减少、合并症相关的临床结果，并且经常延迟截肢。此外，诊所发现的一个主要问题是无法应对康复；即使长期和强化的康复也无法改善功能损伤。康复的基本原则围绕骨骼肌的可塑性，或者说适应感知的机械或化学线索的能力，以提高其功能能力和效率。我们假设 VML 损伤后剩余肌肉的病理生理学限制与缺乏内源性再生能力，例如全身新陈代谢的改善。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并发症，例如代谢不灵活可能与收缩组织的主要丧失一样严重。迄今为止，一个缺乏对伤害自然后遗症的全面了解，特别是对受伤后剩余的肌肉以及破坏性的病理生理变化如何影响其固有特性的肌肉。我们的中心假设是肌肉功能障碍、肌纤维和全身代谢不足和神经肌肉缺陷在剩余的肌肉中创造了一个敌对的细胞环境，减轻肌肉可塑性并削弱再生康复的有效性。我们提出三项具体建议旨在解决这些假设：1）建立神经支配减弱的信号机制 VML 后剩余的肌肉； 2) 确定剩余肌肉氧化适应的细胞机制 VML之后； 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病症，例如肌营养不良症、非营养不良性肌病、和肌肉减少症。