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.

Project Narrative: Spinal cord injury (SCI) generates a cascade of events resulting in loss of voluntary movement and muscle degeneration. This study is innovative because it seeks to slow down this degenerative process through the use of Tamoxifen, early after SCI, and to maintain the contractile properties of skeletal muscles, as well as the appropriate expression of myosin heavy chain proteins in muscle fiber. We will also determine some of the mechanisms activated or de-activated by TAM in muscle cells using metabolomic analyses and if the drug provides an appropriate environment for satellite cell proliferation and/or muscle regeneration in male and female rats, which may lead to novel therapeutic strategies to enhance functional recovery early after SCI.