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. 2018 Jun 7;19(6):1701.
doi: 10.3390/ijms19061701.

Activity-Based Physical Rehabilitation With Adjuvant Testosterone to Promote Neuromuscular Recovery After Spinal Cord Injury

Free PMC article

Activity-Based Physical Rehabilitation With Adjuvant Testosterone to Promote Neuromuscular Recovery After Spinal Cord Injury

Dana M Otzel et al. Int J Mol Sci. .
Free PMC article


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.

Keywords: BDNF; FOXO; IGF-1; PGC-1 alpha; PGC-1 beta; PI3K; bodyweight-supported treadmill training; estradiol; estrogen; motor neuron; muscle; neuroplasticity.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Androgen-mediated Anabolic and Anticatabolic Signaling Pathways in Muscle. Anabolic signaling: Androgens (A) pass through the plasma membrane and bind to cytosolic androgen receptors (AR). Dimerized and phosphorylated ARs pass through the nuclear membrane and bind to a region of the DNA termed the androgen response element (ARE), thereby initiating protein synthesis. Ligand-bound ARs may also enhance Wnt signaling as follows. Wnt binds to Frizzled and in turn disheveled (not shown). Disheveled inhibits the activity of glycogen synthase kinase-3β (GSK3β), which phosphorylates β-catenin and marks it for degradation. When GSK3β is inhibited, β-catenin accumulates and enters the nucleus where it binds to a region of the DNA termed the T-cell factor/lymphoid enhancer factor (TCF/LEF) that regulates genes involved in myogenic differentiation. Ligand-bound ARs enhance Wnt signaling by inhibiting GSK3β and attaching to β-catenin for nuclear shuttling. Androgens may also indirectly stimulate protein synthesis by activating the phosphatidylinositol-3 kinase (PI3K)/Akt signaling through actions of Erk or by promoting synthesis of insulin-like growth factor (IGF)-1 or mechano growth factor (MGF). IGF-1 and MGF bind cell-surface IGF-1 receptors (IGF-1R) and activate PI3K/Akt signaling. Anticatabolic signaling: Activation of PI3K/Akt signaling inhibits the transcription factor forkhead box O (FOXO). FOXO1 and FOXO3a activate muscle atrophy F-box (MAFbx or atrogin-1) and muscle ring finger-1 (MuRF1), and E3 ubiquitin ligases that prepare proteins for proteasome degradation.

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