Exercise promotes recovery after motoneuron injury via hormonal mechanisms

Abstract

Injuries to spinal motoneurons manifest in a variety of forms, including damage to peripheral axons, neurodegenerative disease, or direct insult centrally. Such injuries produce a variety of negative structural and functional changes in both the directly affected and neighboring motoneurons. Exercise is a relatively simple behavioral intervention that has been demonstrated to protect against, and accelerate recovery from, these negative changes. In this article, we describe how exercise is neuroprotective for motoneurons, accelerating axon regeneration following axotomy and attenuating dendritic atrophy following the death of neighboring motoneurons. In both of these injury models, the positive effects of exercise have been found to be dependent on gonadal hormone action. Here we describe a model in which exercise, hormones, and brain-derived neurotrophic factor might all interact to produce neuroprotective effects on motoneuron structure following neural injury.

Keywords: axon regeneration; axotomy; dendritic morphology; exercise; hormones; neuroprotection; neurotrophins.

Figure 1

Motoneuron morphology is protected by gonadal hormones or exercise following the death of neighboring motoneurons. Darkfield digital micrographs of transverse hemisections through the lumbar (L2) spinal cord and computer-generated reconstructions of cholera toxin-conjugated horseradish peroxidase (BHRP)-labeled somata and processes of an untreated male (A, B), and saporin-injected male rats with either no further treatment (C, D), or given exogenous testosterone (E, F), ad libitum exercise (G, H), or ad libitum exercise after orchidectomy (I, J) after BHRP injection into the left vastus lateralis muscle. Treatment with testosterone (E, F) was achieved via Silastic capsule (45 mm long; outer diameter = 3.18 mm; inner diameter = 1.57 mm) implanted subcutaneously (from Little et al., 2009); such implants produce plasma titers of testosterone in the normal physiological range (Smith et al., 1977). Exercised animals (G, H, I, J) had running wheels attached to their home cages, and exercise was ad libitum (from Chew and Sengelaub, 2019 and unpublished data). The treatment periods with testosterone or exercise after saporin injection was four weeks. Computer-generated composites of BHRP labeling were drawn at 480 μm intervals through the entire rostrocaudal extent of the quadriceps motor pool; these composites were selected because they are representative of their respective group average dendritic lengths. Scale bar: 500 µm.

Figure 2

Motoneuron dendritic length is protected by gonadal hormones and exercise following the death of neighboring motoneurons. Dendritic lengths of quadriceps motoneurons in untreated animals (n = 5), saporin-injected animals that either received no further treatment (SAP; n = 6) or were given exogenous testosterone (SAP + T; n = 6), ad libitum exercise (SAP + EXERCISE; n = 6), or ad libitum exercise after orchidectomy (SAP + EXERCISE + ORCH; n = 5). Following saporin-induced motoneuron death, surviving neighboring motoneurons lost almost 64% of their dendritic length. Treatment with physiological testosterone via Silastic capsule (45 mm long; outer diameter = 3.18 mm; inner diameter = 1.57 mm) implanted subcutaneously (Little et al., 2009), or ad libitum running wheel exercise, attenuated this dendritic atrophy (Chew and Sengelaub, 2019); neuroprotective exercise effects were prevented with orchidectomy (Chew and Sengelaub, unpublished). Tissue was collected 4 weeks after SAP injection. Dendritic lengths were reconstructed in three dimensions under darkfield illumination at final magnification of 250× using Neurolucida, and total dendritic length was corrected by the number of BHRP-labeled motoneurons in each animal. Groups were compared using analysis of variance. Bar heights represent mean ± SEM. *indicates significantly different from untreated animals. †indicates significantly different from untreated saporin-injected animals. BHRP: Cholera toxin-conjugated horseradish peroxidase.