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Testosterone dose dependently prevents bone and muscle loss in rodents after spinal cord injury.

ABSTRACT: Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0?mg/week), or (4) SCI+High-dose TE (7.0?mg/week). Twenty-one days post-injury, SCI animals exhibited a 77-85% reduction in hindlimb cancellous bone volume at the distal femur (measured via ?CT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13-27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI.

SUBMITTER: Yarrow JF

PROVIDER: S-EPMC5911705 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Testosterone dose dependently prevents bone and muscle loss in rodents after spinal cord injury.

Yarrow Joshua F JF Conover Christine F CF Beggs Luke A LA Beck Darren T DT Otzel Dana M DM Balaez Alexander A Combs Sarah M SM Miller Julie R JR Ye Fan F Aguirre J Ignacio JI Neuville Kathleen G KG Williams Alyssa A AA Conrad Bryan P BP Gregory Chris M CM Wronski Thomas J TJ Bose Prodip K PK Borst Stephen E SE

Journal of neurotrauma 20140501 9

Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-D ...[more]

PMID: 24378197

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Project description:Spinal cord injury (SCI) results in rapid and extensive sublesional bone loss. Sclerostin, an osteocyte-derived glycoprotein that negatively regulates intraskeletal Wnt signaling, is elevated after SCI and may represent a mechanism underlying this excessive bone loss. However, it remains unknown whether pharmacologic sclerostin inhibition ameliorates bone loss subsequent to SCI. Our primary purposes were to determine whether a sclerostin antibody (Scl-Ab) prevents hindlimb cancellous bone loss in a rodent SCI model and to compare the effects of a Scl-Ab to that of testosterone-enanthate (TE), an agent that we have previously shown prevents SCI-induced bone loss. Fifty-five (n = 11-19/group) skeletally mature male Sprague-Dawley rats were randomized to receive: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe (250 kilodyne) SCI, (C) 250 kilodyne SCI + TE (7.0 mg/wk, im), or (D) 250 kilodyne SCI + Scl-Ab (25 mg/kg, twice weekly, sc) for 3 weeks. Twenty-one days post-injury, SCI animals exhibited reduced hindlimb cancellous bone volume at the proximal tibia (via μCT and histomorphometry) and distal femur (via μCT), characterized by reduced trabecular number and thickness. SCI also reduced trabecular connectivity and platelike trabecular structures, indicating diminished structural integrity of the remaining cancellous network, and produced deficits in cortical bone (femoral diaphysis) strength. Scl-Ab and TE both prevented SCI-induced cancellous bone loss, albeit via differing mechanisms. Specifically, Scl-Ab increased osteoblast surface and bone formation, indicating direct bone anabolic effects, whereas TE reduced osteoclast surface with minimal effect on bone formation, indicating antiresorptive effects. The deleterious microarchitectural alterations in the trabecular network were also prevented in SCI + Scl-Ab and SCI + TE animals, whereas only Scl-Ab completely prevented the reduction in cortical bone strength. Our findings provide the first evidence indicating that sclerostin inhibition represents a viable treatment to prevent SCI-induced cancellous and cortical bone deficits and provides preliminary rationale for future clinical trials focused on evaluating whether Scl-Ab prevents osteoporosis in the SCI population.

Project description:BackgroundMitochondrial health is an important predictor of several health-related comorbidities including obesity, type 2 diabetes mellitus, and cardiovascular disease. In persons with spinal cord injury (SCI), mitochondrial health has been linked to several important body composition and metabolic parameters. However, the complex interplay of how mitochondrial health is affected has yet to be determined in this population.ObjectiveIn this study, we examined the contribution of visceral adiposity, inflammatory biomarkers, testosterone and circulating serum growth factors as predictors of mitochondrial health in persons with chronic SCI.ParticipantsThirty-three individuals with chronic SCI (n = 27 Males, n = 6 Females, age: 40 ± 13.26 years, level of injury: C4-L1, BMI: 23 ± 5.57) participated in this cross-sectional study.MethodsVisceral adipose tissue (VAT) was measured via magnetic resonance imaging (MRI). After an overnight fast, serum testosterone, inflammatory biomarkers [interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), c-reactive protein (CRP)], and anabolic growth factors [insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3)] were measured. Skeletal muscle biopsies were obtained from the vastus lateralis muscle to measure citrate synthase (CS) and Complex III activity. Regression analyses were used to examine predictors of mitochondrial mass and activity.ResultsCS activity was negatively associated with VAT (r 2 = 0.360, p < 0.001), CRP (r 2 = 0.168, p = 0.047), and positively associated with testosterone (r 2 = 0.145, p = 0.042). Complex III activity was negatively associated with VAT relative to total lean mass (VAT:TLM) (r 2 = 0.169, p = 0.033), trended for CRP (r 2 = 0.142, p = 0.069), and positively associated with testosterone (r 2 = 0.224, p = 0.010). Multiple regression showed CS activity was significantly associated with VAT + CRP (r 2 = 0.412, p = 0.008) and VAT + Testosterone (r 2 = 0.433, p = 0.001). Complex III activity was significantly associated with VAT relative to total trunk cross-sectional area (CSA) + CRP (VAT:total trunk CSA + CRP; r 2 = 0.286, p = 0.048) and VAT + Testosterone (r 2 = 0.277, p = 0.024).ConclusionIncreased visceral adiposity and associated inflammatory signaling (CRP) along with reduced testosterone levels predict mitochondrial dysfunction following SCI. Specifically, lower VATCSA and higher testosterone levels or lower VATCSA and lower CRP levels positively predict mitochondrial mass and enzyme activity in persons with chronic SCI. Future research should investigate the efficacy of diet, exercise, and potentially testosterone replacement therapy on enhancing mitochondrial health in chronic SCI.Clinical trial registration[www.ClinicalTrials.gov], identifier: [NCT02660073].

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Testosterone dose dependently prevents bone and muscle loss in rodents after spinal cord injury.

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Testosterone dose dependently prevents bone and muscle loss in rodents after spinal cord injury.

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