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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：
10597639
负责人：
Jarrod A Call
金额：
$ 45.29万
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/10597639
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.

摘要