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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 weight and cross sectional area of hindlimb muscles.WT and SOD1 mice were implanted with either a DHT-filled or an empty silastic tube, or orchidectomized at P75, and the morphological analyses were made at P120. A: In WT mice, DHT increased the GN weight by 7% (212.4±8.8 mg), whereas orchidectomy decreased it by 14% (171.4±9.0 mg) compared with control WT mice (198.4±5.5 mg). In SOD1 mice, DHT increased the GN weight by 32% (147.5±4.5 mg, p = 0.00017), whereas orchidectomy decreased it by 25% (83.4±5.7 mg, p = 0.0086) compared with control SOD1 mice (111.4±6.6 mg). B: In WT mice, DHT increased the weight of TA muscle by 12% (71.2±2.5 mg), whereas orchidectomy decreased it by 12% (56.1±3.6 mg) compared with control WT mice (63.6±1.5 mg). In SOD1 mice, DHT increased the weight of TA muscle by 43% (46.3±2.4 mg, p = 0.0017), whereas orchidectomy decreased it by 22% (25.2±2.4 mg, p = 0.05) compared with control SOD1 mice (32.5±2.5 mg). Sample size is indicated in ( ) for each group. ## p<0.01, ### p<0.01 (compared with age-matched WT mice), ** p<0.01, ***p<0.001 (compared with control SOD1 mice). C: DHT increased the cross-sectional area of TA muscle by 22.3% (3.23±0.19 mm2, n = 3, p = 0.034), whereas orchidectomy decreased it by 20.8% (2.09±0.11 mm2, n = 3, p = 0.008) compared with control SOD1 mice (2.64±0.03 mm2, n = 3). D: DHT did not cause a significant increase in the muscle fiber number (4.8% increase, 3020.7±152.2, p = 0.49). Likewise, orchidectomy did not cause a significant decrease in the muscle fiber number (7.0% decrease, 2681.0±86.9, p = 0.19) compared with control SOD1 mice (2883.7±97.0). E: Representative pictures of the cross sectional area of TA muscles are shown. Scale bar = 50 µm. F: Distribution of the area of single muscle fiber is shown. Per TA muscle, 600–900 muscle fibers were measured, and 3 TA muscles per each treatment group were used for the analysis of muscle fiber area. DHT treatment shifted the area of muscle fibers toward larger areas (1070.8±39.8 µm2, p = 0.032), whereas orchidectomy shifted it toward smaller areas (729.1±61.9 µm2, p = 0.023) compared with control SOD1 mice (904.7±26.6 µm2). Data are mean ± SEM. p<0.001 (2 way-ANOVA).
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pone-0037258-g002: DHT increases whereas orchidectomy decreases the weight and cross sectional area of hindlimb muscles.WT and SOD1 mice were implanted with either a DHT-filled or an empty silastic tube, or orchidectomized at P75, and the morphological analyses were made at P120. A: In WT mice, DHT increased the GN weight by 7% (212.4±8.8 mg), whereas orchidectomy decreased it by 14% (171.4±9.0 mg) compared with control WT mice (198.4±5.5 mg). In SOD1 mice, DHT increased the GN weight by 32% (147.5±4.5 mg, p = 0.00017), whereas orchidectomy decreased it by 25% (83.4±5.7 mg, p = 0.0086) compared with control SOD1 mice (111.4±6.6 mg). B: In WT mice, DHT increased the weight of TA muscle by 12% (71.2±2.5 mg), whereas orchidectomy decreased it by 12% (56.1±3.6 mg) compared with control WT mice (63.6±1.5 mg). In SOD1 mice, DHT increased the weight of TA muscle by 43% (46.3±2.4 mg, p = 0.0017), whereas orchidectomy decreased it by 22% (25.2±2.4 mg, p = 0.05) compared with control SOD1 mice (32.5±2.5 mg). Sample size is indicated in ( ) for each group. ## p<0.01, ### p<0.01 (compared with age-matched WT mice), ** p<0.01, ***p<0.001 (compared with control SOD1 mice). C: DHT increased the cross-sectional area of TA muscle by 22.3% (3.23±0.19 mm2, n = 3, p = 0.034), whereas orchidectomy decreased it by 20.8% (2.09±0.11 mm2, n = 3, p = 0.008) compared with control SOD1 mice (2.64±0.03 mm2, n = 3). D: DHT did not cause a significant increase in the muscle fiber number (4.8% increase, 3020.7±152.2, p = 0.49). Likewise, orchidectomy did not cause a significant decrease in the muscle fiber number (7.0% decrease, 2681.0±86.9, p = 0.19) compared with control SOD1 mice (2883.7±97.0). E: Representative pictures of the cross sectional area of TA muscles are shown. Scale bar = 50 µm. F: Distribution of the area of single muscle fiber is shown. Per TA muscle, 600–900 muscle fibers were measured, and 3 TA muscles per each treatment group were used for the analysis of muscle fiber area. DHT treatment shifted the area of muscle fibers toward larger areas (1070.8±39.8 µm2, p = 0.032), whereas orchidectomy shifted it toward smaller areas (729.1±61.9 µm2, p = 0.023) compared with control SOD1 mice (904.7±26.6 µm2). Data are mean ± SEM. p<0.001 (2 way-ANOVA).

Mentions: To examine whether DHT treatment attenuates skeletal muscle atrophy in SOD1-G93A mice, we measured the weight of gastrocnemius (GN) and tibialis anterior (TA), which are vulnerable muscles in ALS [29], [30]. Muscle atrophy in GN and TA muscles was observed in SOD1-G93A mice by showing a 44% and a 49% decreased muscle weight, respectively, compared with wild-type mice (Fig. 2A and B). DHT treatment increased the GN muscle weight by 32% (SOD1-G93A+DHT: 147.5±4.5 mg, SOD1-G93A: 111.4±6.6 mg, p<0.001, Fig. 2A), and the TA muscle weight by 43% (SOD1-G93A+DHT: 46.3±2.4 mg, SOD1-G93A: 32.5±2.5 mg, p = 0.0017, Fig. 2B). Conversely, orchidectomized SOD1-G93A mice with lower androgen concentration showed a decrease in the muscle weight of GN and TA by 25% and 22%, respectively (GN: 83.4±5.7 mg, TA: 25.2±2.4 mg, Fig. 2A and B). A similar pattern of increase or decrease in muscle weight by DHT treatment or orchidectomy, respectively, was observed in wild-type mice as well (Fig. 2A and B).


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 weight and cross sectional area of hindlimb muscles.WT and SOD1 mice were implanted with either a DHT-filled or an empty silastic tube, or orchidectomized at P75, and the morphological analyses were made at P120. A: In WT mice, DHT increased the GN weight by 7% (212.4±8.8 mg), whereas orchidectomy decreased it by 14% (171.4±9.0 mg) compared with control WT mice (198.4±5.5 mg). In SOD1 mice, DHT increased the GN weight by 32% (147.5±4.5 mg, p = 0.00017), whereas orchidectomy decreased it by 25% (83.4±5.7 mg, p = 0.0086) compared with control SOD1 mice (111.4±6.6 mg). B: In WT mice, DHT increased the weight of TA muscle by 12% (71.2±2.5 mg), whereas orchidectomy decreased it by 12% (56.1±3.6 mg) compared with control WT mice (63.6±1.5 mg). In SOD1 mice, DHT increased the weight of TA muscle by 43% (46.3±2.4 mg, p = 0.0017), whereas orchidectomy decreased it by 22% (25.2±2.4 mg, p = 0.05) compared with control SOD1 mice (32.5±2.5 mg). Sample size is indicated in ( ) for each group. ## p<0.01, ### p<0.01 (compared with age-matched WT mice), ** p<0.01, ***p<0.001 (compared with control SOD1 mice). C: DHT increased the cross-sectional area of TA muscle by 22.3% (3.23±0.19 mm2, n = 3, p = 0.034), whereas orchidectomy decreased it by 20.8% (2.09±0.11 mm2, n = 3, p = 0.008) compared with control SOD1 mice (2.64±0.03 mm2, n = 3). D: DHT did not cause a significant increase in the muscle fiber number (4.8% increase, 3020.7±152.2, p = 0.49). Likewise, orchidectomy did not cause a significant decrease in the muscle fiber number (7.0% decrease, 2681.0±86.9, p = 0.19) compared with control SOD1 mice (2883.7±97.0). E: Representative pictures of the cross sectional area of TA muscles are shown. Scale bar = 50 µm. F: Distribution of the area of single muscle fiber is shown. Per TA muscle, 600–900 muscle fibers were measured, and 3 TA muscles per each treatment group were used for the analysis of muscle fiber area. DHT treatment shifted the area of muscle fibers toward larger areas (1070.8±39.8 µm2, p = 0.032), whereas orchidectomy shifted it toward smaller areas (729.1±61.9 µm2, p = 0.023) compared with control SOD1 mice (904.7±26.6 µm2). Data are mean ± SEM. p<0.001 (2 way-ANOVA).
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pone-0037258-g002: DHT increases whereas orchidectomy decreases the weight and cross sectional area of hindlimb muscles.WT and SOD1 mice were implanted with either a DHT-filled or an empty silastic tube, or orchidectomized at P75, and the morphological analyses were made at P120. A: In WT mice, DHT increased the GN weight by 7% (212.4±8.8 mg), whereas orchidectomy decreased it by 14% (171.4±9.0 mg) compared with control WT mice (198.4±5.5 mg). In SOD1 mice, DHT increased the GN weight by 32% (147.5±4.5 mg, p = 0.00017), whereas orchidectomy decreased it by 25% (83.4±5.7 mg, p = 0.0086) compared with control SOD1 mice (111.4±6.6 mg). B: In WT mice, DHT increased the weight of TA muscle by 12% (71.2±2.5 mg), whereas orchidectomy decreased it by 12% (56.1±3.6 mg) compared with control WT mice (63.6±1.5 mg). In SOD1 mice, DHT increased the weight of TA muscle by 43% (46.3±2.4 mg, p = 0.0017), whereas orchidectomy decreased it by 22% (25.2±2.4 mg, p = 0.05) compared with control SOD1 mice (32.5±2.5 mg). Sample size is indicated in ( ) for each group. ## p<0.01, ### p<0.01 (compared with age-matched WT mice), ** p<0.01, ***p<0.001 (compared with control SOD1 mice). C: DHT increased the cross-sectional area of TA muscle by 22.3% (3.23±0.19 mm2, n = 3, p = 0.034), whereas orchidectomy decreased it by 20.8% (2.09±0.11 mm2, n = 3, p = 0.008) compared with control SOD1 mice (2.64±0.03 mm2, n = 3). D: DHT did not cause a significant increase in the muscle fiber number (4.8% increase, 3020.7±152.2, p = 0.49). Likewise, orchidectomy did not cause a significant decrease in the muscle fiber number (7.0% decrease, 2681.0±86.9, p = 0.19) compared with control SOD1 mice (2883.7±97.0). E: Representative pictures of the cross sectional area of TA muscles are shown. Scale bar = 50 µm. F: Distribution of the area of single muscle fiber is shown. Per TA muscle, 600–900 muscle fibers were measured, and 3 TA muscles per each treatment group were used for the analysis of muscle fiber area. DHT treatment shifted the area of muscle fibers toward larger areas (1070.8±39.8 µm2, p = 0.032), whereas orchidectomy shifted it toward smaller areas (729.1±61.9 µm2, p = 0.023) compared with control SOD1 mice (904.7±26.6 µm2). Data are mean ± SEM. p<0.001 (2 way-ANOVA).
Mentions: To examine whether DHT treatment attenuates skeletal muscle atrophy in SOD1-G93A mice, we measured the weight of gastrocnemius (GN) and tibialis anterior (TA), which are vulnerable muscles in ALS [29], [30]. Muscle atrophy in GN and TA muscles was observed in SOD1-G93A mice by showing a 44% and a 49% decreased muscle weight, respectively, compared with wild-type mice (Fig. 2A and B). DHT treatment increased the GN muscle weight by 32% (SOD1-G93A+DHT: 147.5±4.5 mg, SOD1-G93A: 111.4±6.6 mg, p<0.001, Fig. 2A), and the TA muscle weight by 43% (SOD1-G93A+DHT: 46.3±2.4 mg, SOD1-G93A: 32.5±2.5 mg, p = 0.0017, Fig. 2B). Conversely, orchidectomized SOD1-G93A mice with lower androgen concentration showed a decrease in the muscle weight of GN and TA by 25% and 22%, respectively (GN: 83.4±5.7 mg, TA: 25.2±2.4 mg, Fig. 2A and B). A similar pattern of increase or decrease in muscle weight by DHT treatment or orchidectomy, respectively, was observed in wild-type mice as well (Fig. 2A and B).

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