Focal Estrogen Therapy in Male Rats Promotes Neuronal Survival and Reduces Denervation Atrophy After Spinal Cord Injury via Modulation of β-Catenin and NF-κB.

Spinal cord injury (SCI) initiates a devastating vicious cycle characterized by the secondary degeneration of motor neurons in the spinal cord and progressive denervation atrophy in the skeletal muscle they innervate. While the hormone 17β-estradiol (E2) has recognized neuroprotective properties, its capacity to simultaneously halt the distinct degenerative pathways in both the nervous and muscular systems, remains largely unexplored. This study elucidates a novel, dual mechanism through which E2 coordinately protects the entire motor unit. It was first established that a direct myoprotective role exists for E2 in vitro, demonstrating its ability to attenuate IFN-γ-induced upregulation of reactive oxygen species, the critical atrophy ligands MuRF1 and MAFbx in L6 myoblasts. In a contusion SCI model in male rats, we have demonstrated that E2 treatment comprehensively suppressed post-injury proteolytic and apoptotic signaling in skeletal muscle, thus normalizing the Bax: Bcl-2 and calpain: calpastatin ratios and reducing the expression of MAFbx and MuRF1. Mechanistically, this anti-atrophic effect was driven by the inhibition of NF-κB nuclear translocation in muscle tissue. Furthermore, E2 functionally preserved the neuromuscular junction, reducing the expression of MuRF1 and the denervation marker acetylcholinesterase while restoring presynaptic cholineacetyltransferase. Most significantly, our study demonstrated that focal delivery of a sustained-release E2 formulation directly to the site of the injured spinal cord activated the canonical Wnt/β-catenin pro-survival pathway, as evidenced by the stabilization of β-catenin and AKT proteins and a marked increase in the survival of β-catenin-positive motor neurons. Our findings reveal that E2 therapy confers comprehensive protection after SCI by operating on two fronts: it directly blocks NF-κB-driven proteolysis in skeletal muscle while concurrently activating Wnt/β-catenin signaling to promote motor neuron survival. This coordinated, dual-arm mechanism underscores the significant therapeutic potential of targeted E2 delivery to disrupt the self-perpetuating cycle of neuromuscular degeneration following spinal cord injury in male rats.