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5. Sclerostin Inhibition Prevents Spinal Cord Injury-Induced Cancellous Bone Loss

Author

Beggs, Luke A, Ye, Fan, Ghosh, Payal, Beck, Darren T, Conover, Christine F, Balaez, Alexander, Miller, Julie R, Phillips, Ean G, Zheng, Nigel, Williams, Alyssa A, Aguirre, JIgnacio, Wronski, Thomas J, Bose, Prodip K, Borst, Stephen E, and Yarrow, Joshua F

Subjects
Genetic Markers, Male, Rats, Sprague-Dawley, Random Allocation, Bone Morphogenetic Proteins, Animals, Osteoporosis, Testosterone, X-Ray Microtomography, Article, Biomarkers, Spinal Cord Injuries, Rats
Abstract

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.

Published
2015

6. Testosterone inhibits expression of lipogenic genes in visceral fat by an estrogen-dependent mechanism

Author

Holland, A. Maleah, primary, Roberts, Michael D., additional, Mumford, Petey W., additional, Mobley, C. Brooks, additional, Kephart, Wesley C., additional, Conover, Christine F., additional, Beggs, Luke A., additional, Balaez, Alexander, additional, Otzel, Dana M., additional, Yarrow, Joshua F., additional, Borst, Stephen E., additional, and Beck, Darren T., additional

Published
2016
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7. Myostatin Protein and Muscle Fiber Cross‐Sectional Area are Associated with Increased Muscle Satellite Cell Number in 10 Month Old Fisher 344 Rats Treated with Testosterone and Trenbolone Enanthate

Author

Beck, Darren T., primary, Dalbo, Vincent J., additional, Mobley, C. Brooks, additional, Ballmann, Christopher, additional, Kephart, Wesley C., additional, Fox, Carlton D., additional, Santucci, Vincent A., additional, Beggs, Luke A., additional, Balaez, Alexander, additional, Hoerr, Frederic J., additional, Yarrow, Joshua F., additional, Borst, Stephen E., additional, and Roberts, Michael D., additional

Published
2016
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8. Sclerostin Inhibition Prevents Spinal Cord Injury-Induced Cancellous Bone Loss

Author

Beggs, Luke A, primary, Ye, Fan, additional, Ghosh, Payal, additional, Beck, Darren T, additional, Conover, Christine F, additional, Balaez, Alexander, additional, Miller, Julie R, additional, Phillips, Ean G, additional, Zheng, Nigel, additional, Williams, Alyssa A, additional, Aguirre, JIgnacio, additional, Wronski, Thomas J, additional, Bose, Prodip K, additional, Borst, Stephen E, additional, and Yarrow, Joshua F, additional

Published
2015
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9. Influence of Aromatase Inhibition on the Bone-Protective Effects of Testosterone

Author

Beck, Darren T, primary, Yarrow, Joshua F, additional, Beggs, Luke A, additional, Otzel, Dana M, additional, Ye, Fan, additional, Conover, Christine F, additional, Miller, Julie R, additional, Balaez, Alexander, additional, Combs, Sarah M, additional, Leeper, Alicia M, additional, Williams, Alyssa A, additional, Lachacz, Stephanie A, additional, Zheng, Nigel, additional, Wronski, Thomas J, additional, and Borst, Stephen E, additional

Published
2014
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11. Musculoskeletal and Prostate Effects of Combined Testosterone and Finasteride Administration in Older Hypogonadal Men

Author

Borst, Stephen E., primary, Yarrow, Joshua F., additional, Conover, Christine F., additional, Nseyo, Unyime, additional, Meuleman, John R., additional, Lipinska, Judyta A., additional, Braith, Randy W., additional, Beck, Darren T., additional, Martin, Jeffrey S., additional, Morrow, Matthew, additional, Roessner, Shirley, additional, Beggs, Luke A., additional, McCoy, Sean C., additional, Cannady, Darryl F., additional, and Shuster, Jonathan J., additional

Published
2014
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13. Testosterone Dose Dependently Prevents Bone and Muscle Loss in Rodents after Spinal Cord Injury

Author

Yarrow, Joshua F., primary, Conover, Christine F., additional, Beggs, Luke A., additional, Beck, Darren T., additional, Otzel, Dana M., additional, Balaez, Alexander, additional, Combs, Sarah M., additional, Miller, Julie R., additional, Ye, Fan, additional, Aguirre, J. Ignacio, additional, Neuville, Kathleen G., additional, Williams, Alyssa A., additional, Conrad, Bryan P., additional, Gregory, Chris M., additional, Wronski, Thomas J., additional, Bose, Prodip K., additional, and Borst, Stephen E., additional

Published
2014
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14. Testosterone Dose-Dependently Prevents Bone and Muscle Loss in Rodents Following Spinal Cord Injury

Author

Otzel, Dana M., primary, Conover, Christine F., additional, Beggs, Luke A., additional, Beck, Darren T., additional, Baelez, Alexander, additional, Combs, Sarah M., additional, Miller, Julie R., additional, Ye, Fan, additional, Aguirre, J Ignacio, additional, Neuville, Kathleen G., additional, Williams, Alyssa A., additional, Conrad, Bryan P., additional, Gregory, Chris M., additional, Wronski, Thomas J., additional, Bose, Prodip K., additional, Borst, Stephen E., additional, and Yarrow, Joshua F., additional

Published
2014
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17. Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial

Author

Borst, Stephen E., primary, Yarrow, Joshua F., additional, Conover, Christine F., additional, Nseyo, Unyime, additional, Meuleman, John R., additional, Lipinska, Judyta A., additional, Braith, Randy W., additional, Beck, Darren T., additional, Martin, Jeffrey S., additional, Morrow, Matthew, additional, Roessner, Shirley, additional, Beggs, Luke A., additional, McCoy, Sean C., additional, Cannady, Darryl F., additional, and Shuster, Jonathan J., additional

Published
2014
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18. Effect of Trenbolone enanthate on protein degradation in levator ani/bulbocavernosus (LABC) muscle in orchiectomized rats

Author

Ye, Fan, primary, McCoy, Sean C, additional, Yarrow, Joshua F, additional, Conover, Christine F, additional, Beck, Darren T, additional, Beggs, Luke A, additional, Beharry, Adam W, additional, Judge, Andrew R, additional, Ross, Heather H, additional, Borsa, Paul A, additional, Tillman, Mark D, additional, Conrad, Bryan P, additional, Pingel, Jennifer E, additional, Wronski, Thomas J, additional, Johnson, Sally E, additional, Kristinsson, Hordur G, additional, and Borst, Stephen E, additional

Published
2013
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22. COMPARISON OF MUSCLE ACTIVATION AND KINEMATICS DURING THE DEADLIFT USING A DOUBLE‐PRONATED AND OVERHAND/UNDERHAND GRIP

Author

Beggs, Luke Allen

Subjects
deadlift, electromyography, kinematics, grip, asymmetry, Education
Abstract

This study examined muscle activation and relative joint angles during a conventional deadlift while using either a double‐pronated or overhand/underhand (OU) grip. Ten weight‐trained individuals performed the deadlift with 60% and 80% of their 1‐repetition maximum, with three different grip variations. EMG recordings were taken of the left and right biceps brachii, brachioradialis, upper trapezius, and upper latissimus dorsi. Motion capture was used to measure angles of the wrist, elbow, knee, and hip. With an OU grip, significant bilateral asymmetry was seen in EMG activity of biceps brachii and brachioradialis. Mean wrist and elbow angle also showed significant bilateral asymmetry when using an OU grip. Training recommendations for the OU grip deadlift should emphasize the need to vary which hand is supinated/pronated to avoid muscle imbalances and possible injury. Furthermore, it may be preferential to use a double‐pronated grip to avoid asymmetric training altogether.

Published
2011

23. Testosterone alters iron metabolism and stimulates red blood cell production independently of dihydrotestosterone.

Author

Beggs LA, Yarrow JF, Conover CF, Meuleman JR, Beck DT, Morrow M, Zou B, Shuster JJ, and Borst SE

Subjects
Aged, Aged, 80 and over, Double-Blind Method, Drug Interactions, Erythrocyte Count, Ferritins blood, Finasteride pharmacology, Humans, Iron blood, Male, Middle Aged, Placebos, Testosterone pharmacology, Transferrin analysis, Dihydrotestosterone metabolism, Erythrocytes drug effects, Erythrocytes metabolism, Iron metabolism, Testosterone analogs & derivatives
Abstract

Testosterone (T) stimulates erythropoiesis and regulates iron homeostasis. However, it remains unknown whether the (type II) 5α-reduction of T to dihydrotestosterone (DHT) mediates these androgenic effects, as it does in some other tissues. Our purpose was to determine whether inhibition of type II 5α-reductase (via finasteride) alters red blood cell (RBC) production and serum markers of iron homeostasis subsequent to testosterone-enanthate (TE) administration in older hypogonadal men. Sixty men aged ≥60 yr with serum T <300 ng/dl or bioavailable T <70 ng/dl received treatment with TE (125 mg/wk) vs. vehicle paired with finasteride (5 mg/day) vs. placebo using a 2 × 2 factorial design. Over the course of 12 mo, TE increased RBC count 9%, hematocrit 4%, and hemoglobin 8% while suppressing serum hepcidin 57% (P < 0.001 for all measurements). Most of the aforementioned changes occurred in the first 3 mo of treatment, and finasteride coadministration did not significantly alter any of these effects. TE also reduced serum ferritin 32% (P = 0.002) within 3 mo of treatment initiation without altering iron, transferrin, or transferrin saturation. We conclude that TE stimulates erythropoiesis and alters iron homeostasis independently of the type II 5α-reductase enzyme. These results demonstrate that elevated DHT is not required for androgen-mediated erythropoiesis or for alterations in iron homeostasis that would appear to support iron incorporation into RBCs.

Published
2014
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24. Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial.

Author

Borst SE, Yarrow JF, Conover CF, Nseyo U, Meuleman JR, Lipinska JA, Braith RW, Beck DT, Martin JS, Morrow M, Roessner S, Beggs LA, McCoy SC, Cannady DF 2nd, and Shuster JJ

Subjects
Aged, Body Composition drug effects, Drug Therapy, Combination, Finasteride pharmacology, Humans, Male, Middle Aged, Muscle Strength drug effects, Testosterone pharmacology, Testosterone therapeutic use, Treatment Outcome, Bone Density drug effects, Finasteride therapeutic use, Hypogonadism drug therapy, Muscle, Skeletal drug effects, Prostate drug effects, Testosterone analogs & derivatives
Abstract

Testosterone acts directly at androgen receptors and also exerts potent actions following 5α-reduction to dihydrotestosterone (DHT). Finasteride (type II 5α-reductase inhibitor) lowers DHT and is used to treat benign prostatic hyperplasia. However, it is unknown whether elevated DHT mediates either beneficial musculoskeletal effects or prostate enlargement resulting from higher-than-replacement doses of testosterone. Our purpose was to determine whether administration of testosterone plus finasteride to older hypogonadal men could produce musculoskeletal benefits without prostate enlargement. Sixty men aged ≥60 yr with a serum testosterone concentration of ≤300 ng/dl or bioavailable testosterone ≤70 ng/dl received 52 wk of treatment with testosterone enanthate (TE; 125 mg/wk) vs. vehicle, paired with finasteride (5 mg/day) vs. placebo using a 2 × 2 factorial design. Over the course of 12 mo, TE increased upper and lower body muscle strength by 8-14% (P = 0.015 to <0.001), fat-free mass 4.04 kg (P = 0.032), lumbar spine bone mineral density (BMD) 4.19% (P < 0.001), and total hip BMD 1.96% (P = 0.024) while reducing total body fat -3.87 kg (P < 0.001) and trunk fat -1.88 kg (P = 0.0051). In the first 3 mo, testosterone increased hematocrit 4.13% (P < 0.001). Coadministration of finasteride did not alter any of these effects. Over 12 mo, testosterone also increased prostate volume 11.4 cm(3) (P = 0.0051), an effect that was completely prevented by finasteride (P = 0.0027). We conclude that a higher-than-replacement TE combined with finasteride significantly increases muscle strength and BMD and reduces body fat without causing prostate enlargement. These results demonstrate that elevated DHT mediates testosterone-induced prostate enlargement but is not required for benefits in musculoskeletal or adipose tissue.

Published
2014
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