Estrogen signaling is necessary for exercise‐mediated enhancement of motoneuron participation in axon regeneration after peripheral nerve injury in mice

Abstract

Thousands of people each year suffer from peripheral nerve injury. Treatment options are limited, and recovery is often incomplete. Treadmill exercise can enhance nerve regeneration; however, this appears to occur in a sex-dependent manner. Females respond best to short duration, high speed interval training; whereas, males respond best to slower, continuous training. Previous studies have shown a role for testosterone in this process, but the role of estrogen is unknown. To evaluate the role of estrogen signaling in treadmill exercise, we blocked estrogen receptor (ER) signaling during treadmill exercise in males and female wild type mice. The right common fibular (CF) branch of the sciatic nerve was cut and repaired with fibrin glue that contained the ER antagonist ICI 182,780. Estradiol-filled or blank Silastic capsules were implanted subcutaneously at the time of nerve transection. Starting three days post-transection, exercised mice received treadmill training using the paradigm appropriate to their sex 5 days a week for 2 weeks. Fourteen days after the initial nerve transection, motoneurons whose axons had regenerated at least 1.5 mm distal to the original cut sites were labeled with a retrograde tracer. Regeneration was quantified by counting the number of fluorescent labeled motoneurons in the lumbar region of the spinal cord. Both treadmill training and estradiol administration increased the number of motoneurons participating in axon regeneration, but these effects were blocked by ER antagonist treatment. Estrogen signaling is important for the enhancing effects of treadmill exercise on motoneuron participation after peripheral nerve cut.

Neurotrophic and Neuroregenerative Effects of GH/IGF1

“…The local administration of IGF-1 improves the recovery of facial nerve function after a crush injury [ 128 ]. Furthermore, gonadal hormones [ 129 ], like estradiol [ 130 ] and testosterone [ 131 ] contribute increasing axon regeneration after peripheral nerve section. Tuffaha et al [ 132 ] demonstrated that during GH therapy in mice, the peripheral nerve injury accelerates axonal regeneration and myelination, reduces muscle atrophy, and enhances muscle reinnervation.…”

A network biology approach to unraveling inherited axonopathies

“…Recently, reduced Shh signaling was shown to disturb axon regeneration via misregulated myelin degradation 56 . Estrogen signaling has also been implicated in axon regeneration by accelerating peripheral nerve regeneration and increasing motoneuron participation 57,58 . Another unexpected pathway enriched within the AXONO module was Pathogenic Escherichia Coli infection.…”

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…3). Thus, estradiol enhances axonal regeneration in peripheral nerves (Acosta et al, 2017) and decreases motoneuron axonal loss and promotes motoneuron dendritic growth in the central nervous system in animal models of spinal cord injury (Sengelaub and Xu, 2018). Estradiol also decreases axonal loss in experimental autoimmune encephalomyelitis in rats.…”