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）是一种没有治愈的疾病，其特征是流失感知感知 自愿运动最终导致肌肉萎缩。大多数研究都集中在神经上 再生不是肌肉恢复，尽管神经再生是没有用的 维修。受伤后不久进行运动是一种减少动物模型中肌肉萎缩的常见疗法，但 人类在创伤后的急性阶段不可能。有效的疗法必须减少肌肉 SCI后急性阶段的退化并改善肌肉收缩特性，直到可能进行运动。 我们的实验室正在开创使用FDA批准的癌症药物的他莫昔芬（TAM）的使用，以减少肌肉 创伤后的变性。 TAM是一种选择性的雌激素受体调节剂，可以逆转肌肉的变化 类型组成并减少SCI诱导的对肌肉纤维收缩特性的影响，因为雌二醇， 通过雌激素受体（ER）的工作具有这些作用。此外，TAM具有潜在的好处 可以刺激卫星细胞激活/增殖。 TAM与不同的ERS的相互作用表明 对这种药物的反应可能存在性别差异。由于在 肌肉纤维和收缩特性，为定义TAM对女性和女性的影响是必要的新研究 科学后的雄性肌肉组织。我们的初步数据表明，TAM改善了运动恢复和 防止肌肉组织中的肌球蛋白损失。因此，我们的中心假设是TAM提早给药 SCI之后，将部分保留肌肉纤维的收缩特性，减少变性和 最终增加肌纤维增殖/再生。此外，我们想探索可能的性行为 在这种药物的反应和在肌肉细胞中激活或去激活的代谢谱的差异之后 科学。本项目具有以下目的：目标1。确定TAM的效果以防止减少 在雄性和雌性大鼠SCI后骨骼肌纤维的收缩性质中，并建立 该药物可防止肌肉变性的机制。我们将植入男性和 中度挫伤后的雌性大鼠。比目鱼和胫骨前肌纤维的收缩特性 将在7、14中进行评估，并将研究肌球蛋白重链（MHC）同工型的表达谱。 受伤后28天（DPI）。目标2。评估TAM对肌源性因素的影响和 SCI后，从骨骼肌中增生/再生蛋白增殖/再生蛋白，并确定这些细胞中的影响是否存在 事件特定于性别。 SCI后，将用TAM治疗雄性和雌性大鼠。该药物对 肌原因子（PAX7，Myod和肌蛋白）的比目鱼和胫骨表达，用作卫星标志物 细胞激活或增殖以及与新肌肉纤维形成相关的蛋白质（Desmin和Embryonic MHC）将在7、14和28 DPI进行测试。这些实验及其结果可能导致新的治疗性 SCI后增强肌肉和运动恢复的策略。