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: 10331118
• 负责人: JORGE David MIRANDA
• 金额: $ 36.95万
• 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/10331118
• 关键词: Acute; Aftercare; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Area; Atrophic; Axon; Cell Proliferation; Data; Desmin; Development; Embryo; Environment; Estradiol; Estrogen Receptors; Event; Exercise; FDA approved; Female; Fiber; Human; Implant; Inflammation; Injury; Laboratories; Lead; 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; 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; effective therapy; exercise program; exercise rehabilitation; experimental study; improved; injured; innovation; male; metabolic profile; metabolomics; motor recovery; muscle degeneration; muscle physiology; muscle regeneration; neuron loss; neuronal circuitry; novel therapeutic intervention; preservation; prevent; protein degradation; regenerative; relating to nervous system; 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，以躯体感觉知觉丧失为特征