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.

肌肉和骨质流失是脊髓损伤（SCI）的标志性后果，阻碍了身体康复

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