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: 10840774
• 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/10840774
• 关键词: Acute; Address; Adjuvant; Animals; Area; Biological Availability; Body Weight; Bone Regeneration; Chest; Chronic; Clinical Trials; Combined Modality Therapy; Cultured Cells; Data; Dose; Edible Plants; Eligibility Determination; 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; Oral Administration; Osteogenesis; Outcome; Phase; Phosphorylation; 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; bone; bone loss; bone turnover; circulating biomarkers; clinically relevant; comorbidity; experimental study; fracture risk; improved; insight; male; mechanical load; microCT; multimodality; muscle form; muscle regeneration; nerve supply; neuronal survival; novel; novel therapeutic intervention; overexpression; pharmacologic; 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.

肌肉和骨质流失是阻碍身体康复的脊髓损伤（SCI）的标志性后果 并恶化了健康结果。这种肌肉骨骼下降是由于由 神经系统侮辱，并受到其他因素的加强，包括受损的胰岛素样生长因子（IGF）-1 肌肉和骨骼的信号传导。多因素障碍的存在可能是相对的基础 大多数独立的药理和机械重新加载策略的无效性无效 严重的SCI后骨骼和肌肉。我们的目标是建立结合物理的多模式策略 与辅助IGF-1恢复以促进SCI后肌肉骨骼恢复，从而解决了这两个 废除和合成代谢信号受损。我们的数据表明被动周期训练和体重 支持的跑步机（TM）训练，基于活动的身体康复形式，减少肌肉损失和 中度挫伤SCI后促进啮齿动物的神经可塑性。但是，这些身体康复 严重的SCI后，方案在再生肌肉和骨骼方面相对无效。 IGF-1已知 独立影响肌肉骨骼完整性，这表明这种合成代谢可能代表可行的候选者 改善科学后的身体康复。确实，我们的数据表明肌肉中IGF-1的病毒过表达 在废弃过程中保护肌肉，并在重新加载后促进肌肉和骨骼恢复。此外，病毒IGF- 1表达已显示可促进脊髓横断后皮质脊髓运动神经元的存活， SCI后保留肌肉功能至关重要的效果。但是，病毒IGF-1疗法不高 翻译。为了解决这个问题，我们开发了一种新颖的口服生物利用人类IGF-1 植物（植物-igf-1），并优化了大鼠和小鼠的剂量方案，从而增加了循环IGF-1 300-500％至少12小时，而不会抑制循环葡萄糖。我们还证明了植物 Pro-IgF-1达到骨骼肌，主要目标组织，并且植物-IGF-1磷酸化IGFR 时间和AKT在培养细胞中的时间和剂量依赖性的方式，从而验证生物活性。对于这个建议，我们将 单独评估植物-igf-1并与啮齿动物中的基于活动的身体康复结合 严重的挫伤科学模型，这代表了将这种高度新颖化合物转换为的下一步 SCI人群的临床试验。所有研究将在4个月大的男性和女性Sprague-进行 接受假手术的Dawley大鼠与严重的胸腔（T9）挫伤科学。我们将执行实验 使用直接和延迟的治疗策略来确定预防和再生疗效， 分别提供了对最合适的治疗窗口的见解。我们还将评估 被动（周期）与动态（TM）负载对IGF-1疗效的影响，我们将评估前肢和 后肢肌肉骨骼结局，以确定治疗功效是否需要正常神经或 不受影响的运动活性，仅在严重的T9 SCI之后的前肢中才存在。结果包括： 肌肉横截面区域（通过MRI），肌肉形态（通过免疫组织化学），孤立的肌肉 力学，肌肉IGF-1信号传导，骨体积（通过Microct），骨转换（通过组织形态计量学和 循环标记），比目鱼皮质脊髓运动神经元的形态/分布和血清IGF-1，IGF结合 蛋白3和葡萄糖。该提案有两个具体的目标： AIM 1。评估管理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。确定将基于活动的身体康复与 辅助IGF-1在严重的SCI后长期服用时会再生骨和肌肉。

项目成果

Passive Cycle Training Promotes Bone Recovery after Spinal Cord Injury without Altering Resting-State Bone Perfusion.

被动循环训练可促进脊髓损伤后的骨恢复，而不改变静息状态骨灌注。

• DOI: 10.1249/mss.0000000000003101
• 发表时间: 2023
• 期刊: Medicine and science in sports and exercise
• 影响因子: 4.1
• 作者: Yarrow,JoshuaF;Wnek,RussellD;Conover,ChristineF;Reynolds,MichaelC;Buckley,KinleyH;Kura,JayachandraR;Sutor,TommyW;Otzel,DanaM;Mattingly,AlexJ;Borst,StephenE;Croft,SummerM;Aguirre,JIgnacio;Beck,DarrenT;McCullough,Dani
• 通讯作者: McCullough,Dani