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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 attenuates axonal loss in the phrenic nerve and ventral root of the spinal cord.A: The phrenic nerve at the entry of the diaphragm muscle was sectioned to observe myelinated axons at P120. Representative pictures of the phrenic nerve from WT, control SOD1, and DHT-treated SOD1 mice are shown. B: Quantification of myelinated axon number in the phrenic nerves is shown. The number of myelinated axons in the phrenic nerve of SOD1 mice (184.6±10.9) is about 40% less compared with WT mice (313.0±11.5, p = 0.0003). DHT-treated SOD1 mice showed 26% more myelinated axons (232.3±16.8, p = 0.043) compared with control SOD1 mice. Sample size is indicated in ( ) for each group. *p<0.05 (compared with control SOD1 mice), ### p<0.001 (compared with WT mice). C: Representative cross-sectional pictures of the ventral roots of the spinal cord lumbar 4 segment from WT, control SOD1, DHT-treated SOD1, and orchidectomized SOD1 mice at P120 are shown. D: Quantification of myelinated axon number in the ventral root of the lumbar 4 spinal cord is shown. The total number of myelinated axons in control SOD1 mice (691.2±43.6) is about 30% less compared with that in WT mice (996.5±58.5, p = 0.0012). DHT-treated SOD1 showed 24% more total myelinated axon number compared with control SOD1 mice (859.6±53.4, p = 0.013). Especially, the number of the large caliber axons (≥4 µm) were 43% less in SOD1 mice (404.2±31.1) compared with WT mice (706.5±51.6, p = 0.0005). DHT-treated SOD1 mice showed 36% more large caliber axons (≥4 µm) (547.8±22.2, p = 0.006) compared with control SOD1 mice. Orchidectomized SOD1 mice showed 10% less total myelinated axon number compared with control SOD1 mice (622.3±29.6, p = 0.01). Sample size is indicated in ( ) for each group. Data are mean ± SEM. *p<0.05, ** p<0.01 (compared with the total myelinated axon numbers in SOD1 control), ##p<0.01, ### p<0.001 (compared with the number of large caliber axons in SOD1 control).
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pone-0037258-g006: DHT attenuates axonal loss in the phrenic nerve and ventral root of the spinal cord.A: The phrenic nerve at the entry of the diaphragm muscle was sectioned to observe myelinated axons at P120. Representative pictures of the phrenic nerve from WT, control SOD1, and DHT-treated SOD1 mice are shown. B: Quantification of myelinated axon number in the phrenic nerves is shown. The number of myelinated axons in the phrenic nerve of SOD1 mice (184.6±10.9) is about 40% less compared with WT mice (313.0±11.5, p = 0.0003). DHT-treated SOD1 mice showed 26% more myelinated axons (232.3±16.8, p = 0.043) compared with control SOD1 mice. Sample size is indicated in ( ) for each group. *p<0.05 (compared with control SOD1 mice), ### p<0.001 (compared with WT mice). C: Representative cross-sectional pictures of the ventral roots of the spinal cord lumbar 4 segment from WT, control SOD1, DHT-treated SOD1, and orchidectomized SOD1 mice at P120 are shown. D: Quantification of myelinated axon number in the ventral root of the lumbar 4 spinal cord is shown. The total number of myelinated axons in control SOD1 mice (691.2±43.6) is about 30% less compared with that in WT mice (996.5±58.5, p = 0.0012). DHT-treated SOD1 showed 24% more total myelinated axon number compared with control SOD1 mice (859.6±53.4, p = 0.013). Especially, the number of the large caliber axons (≥4 µm) were 43% less in SOD1 mice (404.2±31.1) compared with WT mice (706.5±51.6, p = 0.0005). DHT-treated SOD1 mice showed 36% more large caliber axons (≥4 µm) (547.8±22.2, p = 0.006) compared with control SOD1 mice. Orchidectomized SOD1 mice showed 10% less total myelinated axon number compared with control SOD1 mice (622.3±29.6, p = 0.01). Sample size is indicated in ( ) for each group. Data are mean ± SEM. *p<0.05, ** p<0.01 (compared with the total myelinated axon numbers in SOD1 control), ##p<0.01, ### p<0.001 (compared with the number of large caliber axons in SOD1 control).

Mentions: To further examine whether the beneficial effect of DHT at NMJs is accompanied by improved morphology in nerves, we checked the phrenic nerve at the entry of the diaphragm muscle. In SOD1-G93A mice, we found about a 40% loss in myelinated axons in the phrenic nerves compared with wild-type mice at P120 [SOD1-G93A:184.6±10.9, WT: 313.0±11.5, p = 0.0003 (Fig. 6A and B)]. Compared with control SOD1-G93A mice, DHT-treated SOD1-G93A mice exhibited 26% more myelinated axons in the phrenic nerves [SOD1-G93A+DHT: 232.3±16.8, p = 0.043 (Fig. 6A 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 attenuates axonal loss in the phrenic nerve and ventral root of the spinal cord.A: The phrenic nerve at the entry of the diaphragm muscle was sectioned to observe myelinated axons at P120. Representative pictures of the phrenic nerve from WT, control SOD1, and DHT-treated SOD1 mice are shown. B: Quantification of myelinated axon number in the phrenic nerves is shown. The number of myelinated axons in the phrenic nerve of SOD1 mice (184.6±10.9) is about 40% less compared with WT mice (313.0±11.5, p = 0.0003). DHT-treated SOD1 mice showed 26% more myelinated axons (232.3±16.8, p = 0.043) compared with control SOD1 mice. Sample size is indicated in ( ) for each group. *p<0.05 (compared with control SOD1 mice), ### p<0.001 (compared with WT mice). C: Representative cross-sectional pictures of the ventral roots of the spinal cord lumbar 4 segment from WT, control SOD1, DHT-treated SOD1, and orchidectomized SOD1 mice at P120 are shown. D: Quantification of myelinated axon number in the ventral root of the lumbar 4 spinal cord is shown. The total number of myelinated axons in control SOD1 mice (691.2±43.6) is about 30% less compared with that in WT mice (996.5±58.5, p = 0.0012). DHT-treated SOD1 showed 24% more total myelinated axon number compared with control SOD1 mice (859.6±53.4, p = 0.013). Especially, the number of the large caliber axons (≥4 µm) were 43% less in SOD1 mice (404.2±31.1) compared with WT mice (706.5±51.6, p = 0.0005). DHT-treated SOD1 mice showed 36% more large caliber axons (≥4 µm) (547.8±22.2, p = 0.006) compared with control SOD1 mice. Orchidectomized SOD1 mice showed 10% less total myelinated axon number compared with control SOD1 mice (622.3±29.6, p = 0.01). Sample size is indicated in ( ) for each group. Data are mean ± SEM. *p<0.05, ** p<0.01 (compared with the total myelinated axon numbers in SOD1 control), ##p<0.01, ### p<0.001 (compared with the number of large caliber axons in SOD1 control).
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pone-0037258-g006: DHT attenuates axonal loss in the phrenic nerve and ventral root of the spinal cord.A: The phrenic nerve at the entry of the diaphragm muscle was sectioned to observe myelinated axons at P120. Representative pictures of the phrenic nerve from WT, control SOD1, and DHT-treated SOD1 mice are shown. B: Quantification of myelinated axon number in the phrenic nerves is shown. The number of myelinated axons in the phrenic nerve of SOD1 mice (184.6±10.9) is about 40% less compared with WT mice (313.0±11.5, p = 0.0003). DHT-treated SOD1 mice showed 26% more myelinated axons (232.3±16.8, p = 0.043) compared with control SOD1 mice. Sample size is indicated in ( ) for each group. *p<0.05 (compared with control SOD1 mice), ### p<0.001 (compared with WT mice). C: Representative cross-sectional pictures of the ventral roots of the spinal cord lumbar 4 segment from WT, control SOD1, DHT-treated SOD1, and orchidectomized SOD1 mice at P120 are shown. D: Quantification of myelinated axon number in the ventral root of the lumbar 4 spinal cord is shown. The total number of myelinated axons in control SOD1 mice (691.2±43.6) is about 30% less compared with that in WT mice (996.5±58.5, p = 0.0012). DHT-treated SOD1 showed 24% more total myelinated axon number compared with control SOD1 mice (859.6±53.4, p = 0.013). Especially, the number of the large caliber axons (≥4 µm) were 43% less in SOD1 mice (404.2±31.1) compared with WT mice (706.5±51.6, p = 0.0005). DHT-treated SOD1 mice showed 36% more large caliber axons (≥4 µm) (547.8±22.2, p = 0.006) compared with control SOD1 mice. Orchidectomized SOD1 mice showed 10% less total myelinated axon number compared with control SOD1 mice (622.3±29.6, p = 0.01). Sample size is indicated in ( ) for each group. Data are mean ± SEM. *p<0.05, ** p<0.01 (compared with the total myelinated axon numbers in SOD1 control), ##p<0.01, ### p<0.001 (compared with the number of large caliber axons in SOD1 control).
Mentions: To further examine whether the beneficial effect of DHT at NMJs is accompanied by improved morphology in nerves, we checked the phrenic nerve at the entry of the diaphragm muscle. In SOD1-G93A mice, we found about a 40% loss in myelinated axons in the phrenic nerves compared with wild-type mice at P120 [SOD1-G93A:184.6±10.9, WT: 313.0±11.5, p = 0.0003 (Fig. 6A and B)]. Compared with control SOD1-G93A mice, DHT-treated SOD1-G93A mice exhibited 26% more myelinated axons in the phrenic nerves [SOD1-G93A+DHT: 232.3±16.8, p = 0.043 (Fig. 6A 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