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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 improves motoneuron survival in SOD1 mice.A: SOD1 mice were implanted with either a DHT-filled or an empty silastic (control) tube at P75, and the lumbar spinal cord (L) 3-L5 was collected at P120, the symptomatic age. Cross-sectional pictures of the hemi-lumbar spinal cord in WT, control SOD1, and DHT-treated SOD1 mice are shown. B: There was a 41% reduction in motoneuron number in the L3–L5 of SOD1 mice (13.9±0.7, n = 5) compared with WT mice at P120 (23.8±0.9, n = 4, p<0.0001). DHT-treated SOD1 mice contained 27% more motoneurons (17.7±0.8, n = 5, p = 0.0093) compared with control SOD1 mice. In the cervical spinal cord, there were 45% less motoneurons in SOD1 mice (16.8±0.7, n = 3, p = 0.015) compared with WT mice at P120 (30.6±1.5, n = 3). There were 18% more motoneurons in DHT-treated SOD1 mice (19.9±0.4, n = 3, p = 0.467) compared with control SOD1 mice. Data are mean ± SEM. **p<0.01(compared with control SOD1 mice), #p<0.05, ### p<0.001 (compared with age-matched WT mice).
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pone-0037258-g007: DHT improves motoneuron survival in SOD1 mice.A: SOD1 mice were implanted with either a DHT-filled or an empty silastic (control) tube at P75, and the lumbar spinal cord (L) 3-L5 was collected at P120, the symptomatic age. Cross-sectional pictures of the hemi-lumbar spinal cord in WT, control SOD1, and DHT-treated SOD1 mice are shown. B: There was a 41% reduction in motoneuron number in the L3–L5 of SOD1 mice (13.9±0.7, n = 5) compared with WT mice at P120 (23.8±0.9, n = 4, p<0.0001). DHT-treated SOD1 mice contained 27% more motoneurons (17.7±0.8, n = 5, p = 0.0093) compared with control SOD1 mice. In the cervical spinal cord, there were 45% less motoneurons in SOD1 mice (16.8±0.7, n = 3, p = 0.015) compared with WT mice at P120 (30.6±1.5, n = 3). There were 18% more motoneurons in DHT-treated SOD1 mice (19.9±0.4, n = 3, p = 0.467) compared with control SOD1 mice. Data are mean ± SEM. **p<0.01(compared with control SOD1 mice), #p<0.05, ### p<0.001 (compared with age-matched WT mice).

Mentions: To examine whether DHT treatment increased motoneuron survival, we labeled the spinal cord sections with a choline acetyltransferase (ChAT) antibody to visualize motoneurons. We found about a 40% reduction in the number of motoneurons in the lumbar spinal cord (L3–L5) of SOD1-G93A mice compared with wild-type mice at P120 [SOD1-G93A: 13.9±0.7, WT: 23.8±0.9, p<0.0001 (Fig. 7A and B)]. Compared with control SOD1-G93A mice, DHT-treated SOD1-G93A mice showed 27% more motoneurons in the lumbar spinal cord [SOD1-G93A+DHT: 17.7±0.8, p = 0.0093 (Fig. 7A and B)]. In the cervical spinal cord, which contains motoneurons innervating the diaphragm muscle, we also found 18% more motoneurons in DHT-treated SOD1-G93A mice compared with control SOD1-G93A mice [SOD1-G93A+DHT: 19.9±0.4, SOD1-G93A: 16.8±0.7, p = 0.47 (Fig. 7 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 improves motoneuron survival in SOD1 mice.A: SOD1 mice were implanted with either a DHT-filled or an empty silastic (control) tube at P75, and the lumbar spinal cord (L) 3-L5 was collected at P120, the symptomatic age. Cross-sectional pictures of the hemi-lumbar spinal cord in WT, control SOD1, and DHT-treated SOD1 mice are shown. B: There was a 41% reduction in motoneuron number in the L3–L5 of SOD1 mice (13.9±0.7, n = 5) compared with WT mice at P120 (23.8±0.9, n = 4, p<0.0001). DHT-treated SOD1 mice contained 27% more motoneurons (17.7±0.8, n = 5, p = 0.0093) compared with control SOD1 mice. In the cervical spinal cord, there were 45% less motoneurons in SOD1 mice (16.8±0.7, n = 3, p = 0.015) compared with WT mice at P120 (30.6±1.5, n = 3). There were 18% more motoneurons in DHT-treated SOD1 mice (19.9±0.4, n = 3, p = 0.467) compared with control SOD1 mice. Data are mean ± SEM. **p<0.01(compared with control SOD1 mice), #p<0.05, ### p<0.001 (compared with age-matched WT mice).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3351454&req=5

pone-0037258-g007: DHT improves motoneuron survival in SOD1 mice.A: SOD1 mice were implanted with either a DHT-filled or an empty silastic (control) tube at P75, and the lumbar spinal cord (L) 3-L5 was collected at P120, the symptomatic age. Cross-sectional pictures of the hemi-lumbar spinal cord in WT, control SOD1, and DHT-treated SOD1 mice are shown. B: There was a 41% reduction in motoneuron number in the L3–L5 of SOD1 mice (13.9±0.7, n = 5) compared with WT mice at P120 (23.8±0.9, n = 4, p<0.0001). DHT-treated SOD1 mice contained 27% more motoneurons (17.7±0.8, n = 5, p = 0.0093) compared with control SOD1 mice. In the cervical spinal cord, there were 45% less motoneurons in SOD1 mice (16.8±0.7, n = 3, p = 0.015) compared with WT mice at P120 (30.6±1.5, n = 3). There were 18% more motoneurons in DHT-treated SOD1 mice (19.9±0.4, n = 3, p = 0.467) compared with control SOD1 mice. Data are mean ± SEM. **p<0.01(compared with control SOD1 mice), #p<0.05, ### p<0.001 (compared with age-matched WT mice).
Mentions: To examine whether DHT treatment increased motoneuron survival, we labeled the spinal cord sections with a choline acetyltransferase (ChAT) antibody to visualize motoneurons. We found about a 40% reduction in the number of motoneurons in the lumbar spinal cord (L3–L5) of SOD1-G93A mice compared with wild-type mice at P120 [SOD1-G93A: 13.9±0.7, WT: 23.8±0.9, p<0.0001 (Fig. 7A and B)]. Compared with control SOD1-G93A mice, DHT-treated SOD1-G93A mice showed 27% more motoneurons in the lumbar spinal cord [SOD1-G93A+DHT: 17.7±0.8, p = 0.0093 (Fig. 7A and B)]. In the cervical spinal cord, which contains motoneurons innervating the diaphragm muscle, we also found 18% more motoneurons in DHT-treated SOD1-G93A mice compared with control SOD1-G93A mice [SOD1-G93A+DHT: 19.9±0.4, SOD1-G93A: 16.8±0.7, p = 0.47 (Fig. 7 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