Activity-Based Physical Rehabilitation with Adjuvant Testosterone to Promote Neuromuscular Recovery after Spinal Cord Injury

Abstract

Neuromuscular impairment and reduced musculoskeletal integrity are hallmarks of spinal cord injury (SCI) that hinder locomotor recovery. These impairments are precipitated by the neurological insult and resulting disuse, which has stimulated interest in activity-based physical rehabilitation therapies (ABTs) that promote neuromuscular plasticity after SCI. However, ABT efficacy declines as SCI severity increases. Additionally, many men with SCI exhibit low testosterone, which may exacerbate neuromusculoskeletal impairment. Incorporating testosterone adjuvant to ABTs may improve musculoskeletal recovery and neuroplasticity because androgens attenuate muscle loss and the slow-to-fast muscle fiber-type transition after SCI, in a manner independent from mechanical strain, and promote motoneuron survival. These neuromusculoskeletal benefits are promising, although testosterone alone produces only limited functional improvement in rodent SCI models. In this review, we discuss the (1) molecular deficits underlying muscle loss after SCI; (2) independent influences of testosterone and locomotor training on neuromuscular function and musculoskeletal integrity post-SCI; (3) hormonal and molecular mechanisms underlying the therapeutic efficacy of these strategies; and (4) evidence supporting a multimodal strategy involving ABT with adjuvant testosterone, as a potential means to promote more comprehensive neuromusculoskeletal recovery than either strategy alone.

Locomotor training with adjuvant testosterone preserves cancellous bone and promotes muscle plasticity in male rats after severe spinal cord injury

“…Bone loss, muscle loss, and impaired muscle contractile properties are hallmarks of SCI (Biering‐Sorensen et al, ) that contribute to the high fracture risk in this population (Cirnigliaro et al, ). Reduced weight bearing and low testosterone (Abilmona et al, ) are factors that influence these bone and muscle deficits, suggesting that combinatory therapies addressing both impairments may enhance musculoskeletal recovery after motor‐incomplete SCI (Otzel, Lee, et al, ). To address this possibility, we conducted two preliminary studies to examine the acute effects of a standardized quadrupedal bodyweight‐supported TM training regimen (two 20‐min bouts/day, 5 days/week) on recovery of cancellous bone microstructural variables and muscle mass in skeletally mature rodents after severe SCI.…”

“…Interestingly, Lin et al reported that young female rodents exhibited a degree of spontaneous locomotor improvement after severe SCI that was comparable to that observed in our male SCI+TE+TM animals. As discussed above, intersex comparison of functional recovery after SCI is confounded by the potential neuroprotective effects of higher estradiol in females (Otzel, Lee, et al, ). We observed no differences in circulating estradiol among groups in our main study and no associations among estradiol and BBB scores.…”

“…SCI also produces severe bone mineral density (BMD) deficits and deleterious alterations to skeletal microarchitecture in the unloaded limbs, which contribute to increased fracture risk (McCarthy, Bloomer, Gall, Keen, & Ferguson‐Pell, ). These musculoskeletal deficits are exacerbated by the unloading and/or paralysis that occurs secondary to the central nervous system (CNS) injury (Otzel, Lee, Ye, Borst, & Yarrow, ). Specialized activity‐based physical rehabilitation regimens that focus on locomotor retraining (e.g., bodyweight‐supported treadmill training [TM]) have shown promise in hastening muscular recovery in persons with incomplete SCI (Harkema, Schmidt‐Read, Lorenz, Edgerton, & Behrman, ).…”

“…SCI also produces severe bone mineral density (BMD) deficits and deleterious alterations to skeletal microarchitecture in the unloaded limbs, which contribute to increased fracture risk (McCarthy, Bloomer, Gall, Keen, & Ferguson-Pell, 2012). These musculoskeletal deficits are exacerbated by the unloading and/or paralysis that occurs secondary to the central nervous system (CNS) injury (Otzel, Lee, Ye, Borst, & Yarrow, 2018).…”

Up-regulation of MicroRNAs-21 and -223 in a Sprague-Dawley Rat Model of Traumatic Spinal Cord Injury

“…The secondary parenchymal damage is of prolonged nature, based on which candidate treatment modalities have been developed [13][14][15][16]. The severity of the initial TSCI may serve as an indicator of the characteristics and degree of the secondary response; it may also be used to determine optimal treatment modalities [17,18].…”