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.
