Locomotor Training with Anabolic Adjuvants for Musculoskeletal Recovery After SCI

使用合成代谢佐剂进行运动训练以促进 SCI 后的肌肉骨骼恢复

• 批准号: 10407486
• 负责人: Joshua F. Yarrow
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407486
• 关键词: Acute; Address; Adjuvant; Animals; Area; Bone Regeneration; Chest; Chronic; Clinical Trials; Combined Modality Therapy; Cultured Cells; Data; Dose; Edible Plants; Ensure; Female; Forelimb; Fracture; Glucose; Goals; Health; Health Expenditures; Healthcare Systems; Hindlimb; Human; Immunohistochemistry; Impairment; Individual; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Locomotor training; Magnetic Resonance Imaging; Mechanics; Metabolic; Modality; Modeling; Morphology; Motor Activity; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Musculoskeletal; Natural regeneration; Neurologic; Neuronal Plasticity; Oral; Osteogenesis; Outcome; Pharmacology; Phase; Physical Rehabilitation; Plants; Population; Proteins; Rattus; Recovery; Regimen; Rehabilitation therapy; Rodent; Serum; Signal Transduction; Skeletal Muscle; Soleus Muscle; Spinal Cord Contusions; Spinal Cord transection injury; Spinal cord injury; Sprague-Dawley Rats; Stimulus; Time; Tissues; Training; Translating; Translations; Treatment Efficacy; Viral; base; bone; bone loss; bone turnover; circulating biomarkers; clinically relevant; comorbidity; experimental study; fracture risk; improved; insight; male; mechanical load; microCT; multimodality; muscle form; nerve supply; novel; novel therapeutic intervention; overexpression; preservation; primary outcome; regenerative; sex; sham surgery; skeletal; substantia spongiosa; treadmill training; treatment strategy

Muscle and bone loss are hallmark consequences of spinal cord injury (SCI) that impede physical rehabilitation and worsen health outcomes. This musculoskeletal decline is precipitated by disuse resulting from the neurologic insult and is intensified by other factors, including impaired insulin-like growth factor (IGF)-1 signaling in muscle and bone. The presence of multifactorial impairments likely underlies the relative ineffectiveness of most stand-alone pharmacologic and mechanical reloading strategies in regenerating both bone and muscle after severe SCI. Our goal is to establish a multimodal strategy combining physical rehabilitation with adjuvant IGF-1 to promote musculoskeletal recovery after SCI, thus addressing both the disuse and the impaired anabolic signaling. Our data indicate that passive Cycle training and bodyweight supported treadmill (TM) training, forms of activity-based physical rehabilitation, reduce muscle loss and promote neuroplasticity in rodents after moderate contusion SCI. However, these physical rehabilitation regimens are relatively ineffective in regenerating muscle and bone after severe SCI. IGF-1 is known to independently influence musculoskeletal integrity, suggesting this anabolic may represent a viable candidate to improve physical rehabilitation after SCI. Indeed, our data indicate that viral overexpression of IGF-1 in muscle protects muscle during disuse and promotes muscle and bone recovery upon reloading. Additionally, viral IGF- 1 expression has been shown to promote corticospinal motor neuron survival after spinal cord transection, an effect essential to the preservation of muscle function after SCI. However, viral IGF-1 therapies are not highly translational. To address this, we developed a novel orally-bioavailable human IGF-1 expressed in edible plants (Plant-Pro-IGF-1) and optimized a dosing regimen in rats and mice that increases circulating IGF-1 by 300-500% for at least 12 h, without suppressing circulating glucose. We have also demonstrated that Plant- Pro-IGF-1 reaches skeletal muscle, the primary target tissue, and that Plant-Pro-IGF-1 phosphorylates IGFR and Akt in time and dose-dependent manners in cultured cells, validating bioactivity. For this proposal, we will evaluate Plant-Pro-IGF-1 alone and in combination with activity-based physical rehabilitation in our rodent severe contusion SCI model, which represents the next step in translating this highly novel compound to clinical trials in the SCI population. All studies will be conducted in 4-month old male and female Sprague- Dawley rats receiving Sham surgery vs severe mid-thoracic (T9) contusion SCI. We will perform experiments using immediate and delayed treatment strategies to determine preventative and regenerative efficacy, respectively, which provides insight into the most appropriate treatment window. We will also assess the influence of passive (Cycle) vs dynamic (TM) loading on IGF-1 efficacy and we will evaluate forelimb and hindlimb musculoskeletal outcomes to determine if therapeutic efficacy requires normal innervation or unimpaired locomotor activity, factors that are only present in forelimbs after severe T9 SCI. Outcomes include: muscle cross sectional area (via MRI), muscle morphology (via immunohistochemistry), isolated muscle mechanics, muscle IGF-1 signaling, bone volume (via microCT), bone turnover (via histomorphometry and circulating markers), soleus corticospinal motor neuron morphology/distribution, and serum IGF-1, IGF binding protein 3, and glucose. This proposal has two Specific Aims: Aim 1. Evaluate the ability of administered IGF-1 to enhance the acute musculoskeletal effects of activity-based physical rehabilitation in a rodent contusion SCI model. Aim 2. Determine if a multimodal therapy combining activity-based physical rehabilitation with adjuvant IGF-1 regenerates bone and muscle when administered chronically after severe SCI.

肌肉和骨质流失是脊髓损伤 (SCI) 的标志性后果，会阻碍身体康复 并恶化健康结果。这种肌肉骨骼衰退是由于因使用不当而导致的废用而加速的。 神经系统损伤并因其他因素而加剧，包括胰岛素样生长因子 (IGF)-1 受损 肌肉和骨骼中的信号传导。多因素损伤的存在可能是相对的基础 大多数独立的药理学和机械重装策略在再生方面无效 严重 SCI 后的骨骼和肌肉。我们的目标是建立一个结合物理的多式联运策略 使用辅助 IGF-1 进行康复治疗可促进 SCI 后的肌肉骨骼恢复，从而解决 废用和合成代谢信号受损。我们的数据表明，被动自行车训练和体重 支持跑步机 (TM) 训练、基于活动的身体康复形式、减少肌肉损失和 促进啮齿动物中度挫伤 SCI 后的神经可塑性。然而，这些身体康复 严重 SCI 后的肌肉和骨骼再生治疗方案相对无效。 IGF-1 已知 独立影响肌肉骨骼的完整性，表明这种合成代谢可能是一种可行的候选者 改善 SCI 后的身体康复。事实上，我们的数据表明肌肉中 IGF-1 的病毒过度表达 在废弃期间保护肌肉，并在重新装载时促进肌肉和骨骼恢复。此外，病毒IGF- 1 表达已被证明可促进脊髓横断后皮质脊髓运动神经元的存活， 对于 SCI 后保留肌肉功能至关重要。然而，病毒 IGF-1 疗法的效果并不理想。 翻译的。为了解决这个问题，我们开发了一种新型口服生物可利用的人类 IGF-1，以食用形式表达。 植物 (Plant-Pro-IGF-1) 并优化了大鼠和小鼠的给药方案，通过增加循环 IGF-1 300-500% 至少 12 小时，而不抑制循环葡萄糖。我们还证明了植物- Pro-IGF-1 到达骨骼肌（主要靶组织），并且 Plant-Pro-IGF-1 磷酸化 IGFR 和 Akt 在培养细胞中以时间和剂量依赖性方式检测，验证生物活性。对于这个提案，我们将 在我们的啮齿动物中单独评估 Plant-Pro-IGF-1 以及与基于活动的身体康复相结合 严重挫伤 SCI 模型，代表着将这种高度新颖的化合物转化为 SCI 人群的临床试验。所有研究都将在 4 个月大的雄性和雌性 Sprague 中进行 Dawley 大鼠接受假手术与严重中胸 (T9) 挫伤 SCI。我们将进行实验 使用立即和延迟治疗策略来确定预防和再生功效， 分别，这提供了对最合适的治疗窗口的深入了解。我们还将评估 被动（循环）与动态（TM）负载对 IGF-1 功效的影响，我们将评估前肢和 后肢肌肉骨骼结果以确定治疗效果是否需要正常的神经支配或 运动活动未受损，这些因素仅在严重 T9 SCI 后出现在前肢中。结果包括： 肌肉横截面积（通过 MRI）、肌肉形态（通过免疫组织化学）、分离肌肉 力学、肌肉 IGF-1 信号传导、骨量（通过 microCT）、骨转换（通过组织形态计量学和 循环标记物）、比目鱼肌皮质脊髓运动神经元形态/分布、血清 IGF-1、IGF 结合 蛋白质3和葡萄糖。该提案有两个具体目标： 目标 1. 评估施用 IGF-1 增强急性肌肉骨骼效应的能力 啮齿动物挫伤 SCI 模型中基于活动的身体康复。 目标 2. 确定是否采用将基于活动的身体康复与 严重 SCI 后长期服用 IGF-1 佐剂可使骨骼和肌肉再生。