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Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice.

Yoo YE, Ko CP - PLoS ONE (2012)

Bottom Line: We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS.DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport.Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.

View Article: PubMed Central - PubMed

Affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.

ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.

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DHT increases whereas orchidectomy decreases the seminal vesicle weight in wild-type and SOD1-G93A mice.A: The weight of seminal vesicles was measured after removing the adhering tissue and fluid. Wild type (WT) mice and SOD1-G93A (SOD1) mice were implanted with either a DHT-filled or an empty silastic tube. Orchidectomy and/or silastic tube implant was performed at postnatal day 75 (P75), and the seminal vesicle weight was measured at P120. DHT-treated WT mice showed a 19% increase in seminal vesicle weight (156±10.6 mg, p = 0.042) compared with control WT mice (132.1±6.4 mg). In SOD1 mice, the DHT-filled silastic tube also increased the seminal vesicle weight by 38% (146.1±5.5 mg, p = 0.0003) compared with control SOD1 mice (105.8±4.6 mg). Conversely, orchidectomy decreased the seminal vesicle weight in both WT mice (28.4±13 mg, p<0.0001) and SOD1 mice (20.8±3.5 mg, p<0.0001) compared with control WT and SOD1 mice, respectively. SOD1 control mice showed 20% reduced seminal vesicle weight compared with WT control mice (p = 0.0039). Sample size is indicated in ( ) for each group. Data are mean ± SEM. # p<0.05, ### p<0.001 (compared with age-matched WT mice), ** p<0.01, ***p<0.001 (compared with control SOD1 mice). B: WT and SOD1 mice were implanted with either a DHT-filled or an empty silastic tube at P75, and the seminal vesicles were obtained at P120. Representative pictures of the seminal vesicles are shown. Scale bar = 5 mm.
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pone-0037258-g001: DHT increases whereas orchidectomy decreases the seminal vesicle weight in wild-type and SOD1-G93A mice.A: The weight of seminal vesicles was measured after removing the adhering tissue and fluid. Wild type (WT) mice and SOD1-G93A (SOD1) mice were implanted with either a DHT-filled or an empty silastic tube. Orchidectomy and/or silastic tube implant was performed at postnatal day 75 (P75), and the seminal vesicle weight was measured at P120. DHT-treated WT mice showed a 19% increase in seminal vesicle weight (156±10.6 mg, p = 0.042) compared with control WT mice (132.1±6.4 mg). In SOD1 mice, the DHT-filled silastic tube also increased the seminal vesicle weight by 38% (146.1±5.5 mg, p = 0.0003) compared with control SOD1 mice (105.8±4.6 mg). Conversely, orchidectomy decreased the seminal vesicle weight in both WT mice (28.4±13 mg, p<0.0001) and SOD1 mice (20.8±3.5 mg, p<0.0001) compared with control WT and SOD1 mice, respectively. SOD1 control mice showed 20% reduced seminal vesicle weight compared with WT control mice (p = 0.0039). Sample size is indicated in ( ) for each group. Data are mean ± SEM. # p<0.05, ### p<0.001 (compared with age-matched WT mice), ** p<0.01, ***p<0.001 (compared with control SOD1 mice). B: WT and SOD1 mice were implanted with either a DHT-filled or an empty silastic tube at P75, and the seminal vesicles were obtained at P120. Representative pictures of the seminal vesicles are shown. Scale bar = 5 mm.

Mentions: We used a DHT-filled silastic tube, which is an extensively used method to release hormones systemically [17], [25], to increase the concentration of DHT in our study. We thus first tested whether the implant can successively administrate DHT by implanting DHT-filled tubes in wild-type mice at postnatal day 75 (P75). Empty silastic tubes were also implanted in age-matched littermates, which served as a control to exclude any possible artifact caused by the implant surgery. To examine whether the DHT implant increased androgen concentration, the weight of seminal vesicles was measured at P120. Compared to a direct measurement of DHT concentration in serum, which can be affected by anesthesia and stress during blood collection [27], [28], measuring the seminal vesicle weight is a sensitive, albeit indirect, way to assess the androgen level [13]. As shown in Fig. 1A and B, DHT treatment in wild-type mice caused about a 20% increase in the seminal vesicle weight compared with control wild-type mice. As a reverse way to examine the sensitivity of the seminal vesicle to androgen concentration, we attempted to decrease androgen concentration by performing orchidectomy in wild-type mice, and checked whether the seminal vesicle weight decreased. After removing at P75 both testicles, which generate androgens, we found a 79% reduction in the seminal vesicle weights in wild-type mice (Fig. 1A), indicating that the seminal vesicle weight is sensitive to androgen concentration. DHT implant in orchidectomized wild-type mice recovered the seminal vesicle weight to the normal level (Fig. 1A), which confirms a successful administration of DHT through the implant.


Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice.

Yoo YE, Ko CP - PLoS ONE (2012)

DHT increases whereas orchidectomy decreases the seminal vesicle weight in wild-type and SOD1-G93A mice.A: The weight of seminal vesicles was measured after removing the adhering tissue and fluid. Wild type (WT) mice and SOD1-G93A (SOD1) mice were implanted with either a DHT-filled or an empty silastic tube. Orchidectomy and/or silastic tube implant was performed at postnatal day 75 (P75), and the seminal vesicle weight was measured at P120. DHT-treated WT mice showed a 19% increase in seminal vesicle weight (156±10.6 mg, p = 0.042) compared with control WT mice (132.1±6.4 mg). In SOD1 mice, the DHT-filled silastic tube also increased the seminal vesicle weight by 38% (146.1±5.5 mg, p = 0.0003) compared with control SOD1 mice (105.8±4.6 mg). Conversely, orchidectomy decreased the seminal vesicle weight in both WT mice (28.4±13 mg, p<0.0001) and SOD1 mice (20.8±3.5 mg, p<0.0001) compared with control WT and SOD1 mice, respectively. SOD1 control mice showed 20% reduced seminal vesicle weight compared with WT control mice (p = 0.0039). Sample size is indicated in ( ) for each group. Data are mean ± SEM. # p<0.05, ### p<0.001 (compared with age-matched WT mice), ** p<0.01, ***p<0.001 (compared with control SOD1 mice). B: WT and SOD1 mice were implanted with either a DHT-filled or an empty silastic tube at P75, and the seminal vesicles were obtained at P120. Representative pictures of the seminal vesicles are shown. Scale bar = 5 mm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3351454&req=5

pone-0037258-g001: DHT increases whereas orchidectomy decreases the seminal vesicle weight in wild-type and SOD1-G93A mice.A: The weight of seminal vesicles was measured after removing the adhering tissue and fluid. Wild type (WT) mice and SOD1-G93A (SOD1) mice were implanted with either a DHT-filled or an empty silastic tube. Orchidectomy and/or silastic tube implant was performed at postnatal day 75 (P75), and the seminal vesicle weight was measured at P120. DHT-treated WT mice showed a 19% increase in seminal vesicle weight (156±10.6 mg, p = 0.042) compared with control WT mice (132.1±6.4 mg). In SOD1 mice, the DHT-filled silastic tube also increased the seminal vesicle weight by 38% (146.1±5.5 mg, p = 0.0003) compared with control SOD1 mice (105.8±4.6 mg). Conversely, orchidectomy decreased the seminal vesicle weight in both WT mice (28.4±13 mg, p<0.0001) and SOD1 mice (20.8±3.5 mg, p<0.0001) compared with control WT and SOD1 mice, respectively. SOD1 control mice showed 20% reduced seminal vesicle weight compared with WT control mice (p = 0.0039). Sample size is indicated in ( ) for each group. Data are mean ± SEM. # p<0.05, ### p<0.001 (compared with age-matched WT mice), ** p<0.01, ***p<0.001 (compared with control SOD1 mice). B: WT and SOD1 mice were implanted with either a DHT-filled or an empty silastic tube at P75, and the seminal vesicles were obtained at P120. Representative pictures of the seminal vesicles are shown. Scale bar = 5 mm.
Mentions: We used a DHT-filled silastic tube, which is an extensively used method to release hormones systemically [17], [25], to increase the concentration of DHT in our study. We thus first tested whether the implant can successively administrate DHT by implanting DHT-filled tubes in wild-type mice at postnatal day 75 (P75). Empty silastic tubes were also implanted in age-matched littermates, which served as a control to exclude any possible artifact caused by the implant surgery. To examine whether the DHT implant increased androgen concentration, the weight of seminal vesicles was measured at P120. Compared to a direct measurement of DHT concentration in serum, which can be affected by anesthesia and stress during blood collection [27], [28], measuring the seminal vesicle weight is a sensitive, albeit indirect, way to assess the androgen level [13]. As shown in Fig. 1A and B, DHT treatment in wild-type mice caused about a 20% increase in the seminal vesicle weight compared with control wild-type mice. As a reverse way to examine the sensitivity of the seminal vesicle to androgen concentration, we attempted to decrease androgen concentration by performing orchidectomy in wild-type mice, and checked whether the seminal vesicle weight decreased. After removing at P75 both testicles, which generate androgens, we found a 79% reduction in the seminal vesicle weights in wild-type mice (Fig. 1A), indicating that the seminal vesicle weight is sensitive to androgen concentration. DHT implant in orchidectomized wild-type mice recovered the seminal vesicle weight to the normal level (Fig. 1A), which confirms a successful administration of DHT through the implant.

Bottom Line: We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS.DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport.Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.

View Article: PubMed Central - PubMed

Affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.

ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.

Show MeSH
Related in: MedlinePlus