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，其特点是体感丧失 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，尽管如果肌肉退化超出了神经再生的范围，神经再生就毫无用处 维修。在动物模型中，受伤后立即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 脊髓损伤后急性期的退化并改善肌肉收缩特性，直到可以进行运动为止。 我们的实验室正在率先使用他莫昔芬 (TAM)（一种 FDA 批准的抗癌药物）来减少肌肉 创伤后退化。 TAM 是一种选择性雌激素受体调节剂，可以逆转肌肉的变化 类型成分并减少 SCI 引起的对肌纤维收缩特性的影响，因为雌二醇， 通过雌激素受体（ER）发挥作用，具有这些作用。此外，TAM 的潜在优势是 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。由于已经观察到性别差异 肌肉纤维和收缩特性，需要新的研究来确定 TAM 对女性和女性的影响 SCI 后的男性肌肉组织。我们的初步数据表明 TAM 可以改善运动恢复并 防止肌肉组织中肌球蛋白的损失。因此，我们的中心假设是，早期施用 TAM SCI 后，将部分保留肌纤维的收缩特性，减少退化，并且 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 对这种药物的反应以及肌肉细胞激活或失活后的代谢特征的差异 SCI。本项目有以下目标： 目标 1. 确定 TAM 防止减少的效果 雄性和雌性大鼠 SCI 后骨骼肌纤维的收缩特性，并建立 该药物防止肌肉退化的机制。我们将在男性和女性体内植入 TAM 颗粒 中度挫伤 SCI 后的雌性大鼠。比目鱼肌和胫骨前肌纤维的收缩特性 将在 7、14 和 7 进行评估并研究肌球蛋白重链 (MHC) 亚型的表达谱 受伤后 28 天 (DPI)。目的 2. 评估 TAM 对生肌因子和肌源性因子的影响 SCI 后骨骼肌中的增殖/再生蛋白，并确定这些细胞中的影响是否 事件是针对特定性别的。雄性和雌性大鼠在 SCI 后接受 TAM 治疗。这种药物的作用对 比目鱼肌和胫骨肌生肌因子（Pax7、MyoD 和肌生成素）的表达，用作卫星标记 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 下进行测试。这些实验及其结果可能会带来新的治疗方法 增强 SCI 后肌肉和运动恢复的策略。