Effects of Tamoxifen in skeletal muscle recovery after spinal cord injury and mechanisms activated by the drug

他莫昔芬对脊髓损伤后骨骼肌恢复的影响及其激活机制

• 批准号: 10599843
• 负责人: JORGE David MIRANDA
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599843
• 关键词: Acute; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Area; Atrophic; Axon; Cell Proliferation; Data; Desmin; Development; Devices; Embryo; Environment; Estradiol; Estrogen Receptors; Event; Exercise; FDA approved; Female; Fiber; Human; Implant; Inflammation; Injury; Laboratories; Locomotor Recovery; Metabolic; Molecular; Motor Activity; Movement; Muscle; Muscle Cells; Muscle Fibers; Muscular Atrophy; Myogenin; Myosin ATPase; Myosin Heavy Chains; Natural regeneration; Nerve; Nerve Regeneration; Nerve Tissue; Pain; Paralysed; Pathway interactions; Patients; Perception; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Process; Proliferating; Property; Protein Isoforms; Proteins; Rattus; Recovery; Recovery of Function; Reporting; Research; Research Personnel; Selective Estrogen Receptor Modulators; Sex Differences; Skeletal Muscle; Soleus Muscle; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Tamoxifen; Testing; Therapeutic; Tissues; Trauma; cell regeneration; effective therapy; exercise program; exercise rehabilitation; experimental study; improved; injured; innovation; male; metabolic profile; metabolomics; motor recovery; muscle degeneration; muscle physiology; muscle regeneration; neural; neuron loss; neuronal circuitry; novel therapeutic intervention; preservation; prevent; protein degradation; regenerative; repaired; response; satellite cell; sex; sexual dimorphism; somatosensory; tibialis anterior muscle; treatment effect

Spinal cord injury (SCI) is a condition without a cure, characterized by the loss of somatosensory perception and voluntary movement eventually resulting in muscle atrophy. Most research has focused on nerve regeneration not muscle recovery, although nerve regeneration is useless if muscle deterioration is beyond repair. Exercise soon after the injury is a common therapy to reduce muscle atrophy in animal models, but in humans it is not possible in the acute phase after trauma. An effective therapy must reduce muscle degeneration and improve muscle contractile properties in the acute phase after SCI until exercise is possible. Our laboratory is pioneering the use of tamoxifen (TAM), an FDA-approved cancer drug, to reduce muscle degeneration after trauma. TAM, a selective estrogen receptor modulator, could reverse the changes in muscle type composition and reduce the SCI-induced effect on muscle fiber contractile properties because estradiol, working through estrogen receptors (ER), has these effects. In addition, TAM has the potential benefit that it could stimulate Satellite cell activation/proliferation. The interaction of TAM with different ERs suggests that there is a possible sex difference in the response to this drug. Since sexual differences have been observed in muscle fibers and contractile properties, new studies are necessary to define the effect of TAM in female and male muscle tissue after SCI. Our preliminary data demonstrate that TAM improves locomotor recovery and prevents myosin loss in muscle tissue. Therefore, our central hypothesis is that TAM, administered early after SCI, will partially preserve the contractile properties of muscle fibers, reducing degeneration, and ultimately increase myofiber proliferation/regeneration. In addition, we want to explore a possible sex difference in the response to this drug and the metabolic profile activated or de-activated in muscle cells after SCI. The present project has the following aims: AIM 1. To determine the effect of TAM to prevent a reduction in the contractile properties of skeletal muscle fibers after SCI in male and female rats, and establish the mechanisms by which this drug prevents muscle degeneration. We will implant TAM pellets in male and female rats after a moderate contusion SCI. Contractile properties of Soleus and Tibialis anterior muscle fibers will be evaluated and the expression profile of myosin heavy chain (MHC) isoforms will be studied at 7, 14, and 28 days post-injury (DPI). AIM 2. To evaluate the effect of TAM on myogenic factors and proliferative/regenerative proteins from skeletal muscle after SCI and establish if the effects in these cellular events are sex-specific. Male and female rats will be treated with TAM after SCI. The effect of this drug on Soleus and Tibialis expression of myogenic factors (Pax7, MyoD and myogenin), used as markers of Satellite cell activation or proliferation and proteins associated to new muscle fiber formation (desmin and embryonic MHC) will be tested at 7, 14, and 28 DPI. These experiments and their results may lead to novel therapeutic strategies that enhance muscle and locomotor recovery after SCI.

脊髓损伤（SCI）是一种无法治愈的疾病，其特征是躯体感觉丧失 和随意运动，最终导致肌肉萎缩。大多数研究都集中在神经 再生不是肌肉恢复，虽然神经再生是无用的，如果肌肉退化是超越 修复.在动物模型中，受伤后不久进行锻炼是减少肌肉萎缩的常见疗法，但在 人类在创伤后的急性期是不可能的。有效的治疗必须减少肌肉 在脊髓损伤后的急性期，直到运动成为可能，都能改善肌肉的收缩特性。 我们的实验室率先使用FDA批准的抗癌药物他莫昔芬（TAM）来减少肌肉 创伤后的退化TAM是一种选择性雌激素受体调节剂，可以逆转肌肉的变化， 型组合物并降低SCI诱导的对肌纤维收缩性能的影响， 通过雌激素受体（ER）发挥作用，具有这些作用。此外，TAM还有一个潜在的好处， 可以刺激卫星细胞活化/增殖。TAM与不同ER的相互作用表明， 对这种药物的反应可能存在性别差异。由于性别差异已被观察到， 肌肉纤维和收缩特性，有必要进行新的研究来确定TAM对女性的影响， SCI后的男性肌肉组织。我们的初步数据表明，TAM改善运动恢复， 防止肌肉组织中的肌球蛋白丢失。因此，我们的中心假设是，TAM，早期给药， SCI后，将部分保留肌肉纤维的收缩特性，减少退化， 最终增加肌纤维增殖/再生。此外，我们想探索一种可能的性别 对这种药物的反应和代谢谱的差异在肌肉细胞中激活或失活后， SCI.本项目有以下目标：AIM 1。确定TAM对防止降低 在雄性和雌性大鼠脊髓损伤后骨骼肌纤维的收缩特性，并建立 这种药物防止肌肉退化的机制。我们将在男性体内植入TAM颗粒， 雌性大鼠中度挫伤后脊髓损伤。比目鱼肌和胫骨前肌肌纤维的收缩特性 将在7、14和16小时进行评价，并研究肌球蛋白重链（MHC）亚型的表达谱。 伤后28天（DPI）。AIM 2.评价TAM对肌源性因子的影响， 从SCI后骨骼肌中提取增殖/再生蛋白，并确定这些细胞中的作用 事件具有性别特异性。雄性和雌性大鼠将在SCI后用TAM处理。这种药物对 比目鱼肌和胫骨肌生肌因子（Pax 7、MyoD和肌生成素）的表达，用作卫星标志物 细胞活化或增殖以及与新肌纤维形成相关的蛋白质（结蛋白和胚胎 MHC）将在7、14和28 DPI进行测试。这些实验及其结果可能会导致新的治疗方法 增强SCI后肌肉和运动恢复的策略。