Limits...
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.

Show MeSH

Related in: MedlinePlus

DHT improves motor performances and survival in SOD1 mice.A: SOD1 mice were implanted with either a DHT-filled or an empty silastic (control) tube at P75, and their motor performances were assessed every 5 days by the rota-rod test. A mouse was placed on the rotating rod at 11 rpm, and the latency until the mouse fell from the rotating rod was recorded in seconds. DHT-treated SOD1 mice (filled square, n = 16) stayed longer on the rotating rod compared with control SOD1 mice (empty circle, n = 22). Data are mean ± SEM. p = 0.043 (2-way ANOVA). B: Hindlimbs were placed into non-toxic paints and a mouse was allowed to walk on a 50 cm- length of paper, and its continuous locomotion was recorded. Representative footprints obtained from DHT-implanted or empty tube-implanted SOD1 mice at P100 are shown. DHT-treated SOD1 mouse (top panel) showed a longer step length without a trace of dragging hindlimb compared with control SOD1 mice (bottom panel). C: Step length was quantified by dividing walking distance by the number of the steps taken within the measured walking distance. DHT-treated SOD1 mice (filled square, n = 6) showed longer step length compared with control SOD1 mice (empty circle, n = 7). p = 0.003 (paired t-test). D: DHT-treated SOD1 mice showed significantly increased survival duration after DHT administration by 11% in DHT-treated SOD1-G93A mice (82.9±2.9 days, n = 18) compared with age-matched control SOD1-G93A mice (74.8±2.2 days, n = 24). E: DHT-treated SOD1 mice showed significantly increased the overall lifespan by 8 days (filled square, 157.9±2.9 days, n = 18) compared with control SOD1 mice (empty circle, 149.8±2.2 days, n = 24). p = 0.0174 (log-rank test).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3351454&req=5

pone-0037258-g008: DHT improves motor performances and survival in SOD1 mice.A: SOD1 mice were implanted with either a DHT-filled or an empty silastic (control) tube at P75, and their motor performances were assessed every 5 days by the rota-rod test. A mouse was placed on the rotating rod at 11 rpm, and the latency until the mouse fell from the rotating rod was recorded in seconds. DHT-treated SOD1 mice (filled square, n = 16) stayed longer on the rotating rod compared with control SOD1 mice (empty circle, n = 22). Data are mean ± SEM. p = 0.043 (2-way ANOVA). B: Hindlimbs were placed into non-toxic paints and a mouse was allowed to walk on a 50 cm- length of paper, and its continuous locomotion was recorded. Representative footprints obtained from DHT-implanted or empty tube-implanted SOD1 mice at P100 are shown. DHT-treated SOD1 mouse (top panel) showed a longer step length without a trace of dragging hindlimb compared with control SOD1 mice (bottom panel). C: Step length was quantified by dividing walking distance by the number of the steps taken within the measured walking distance. DHT-treated SOD1 mice (filled square, n = 6) showed longer step length compared with control SOD1 mice (empty circle, n = 7). p = 0.003 (paired t-test). D: DHT-treated SOD1 mice showed significantly increased survival duration after DHT administration by 11% in DHT-treated SOD1-G93A mice (82.9±2.9 days, n = 18) compared with age-matched control SOD1-G93A mice (74.8±2.2 days, n = 24). E: DHT-treated SOD1 mice showed significantly increased the overall lifespan by 8 days (filled square, 157.9±2.9 days, n = 18) compared with control SOD1 mice (empty circle, 149.8±2.2 days, n = 24). p = 0.0174 (log-rank test).

Mentions: To determine whether the improved morphological features in DHT-treated SOD1-G93A mice would lead to functional improvement, we tested the effects of DHT treatment in motor behavior and survival of SOD1-G93A mice. In addition to the grip-strength analysis (Fig. 3B), which we previously performed in relation to muscle mass, we further employed rota-rod and footprint analyses as more global assessments of functional outcome. The rota-rod test requires an ability to balance on the rotating rod in addition to muscle strength. Although both DHT-treated and control SOD1-G93A mice showed a similar decline of motor function in the rota-rod test, the gap between two groups increased as disease progressed (Fig. 8A). For example, DHT-treated SOD1-G93A mice stayed 40% longer on the rotating rod compared to control SOD1-G93A mice at P140 (Fig. 8A, p = 0.043). To perform footprint analysis, which are used to detect impaired motor behavior [43], the paws of SOD1-G93A mice were placed into non-toxic paints and allowed to walk on a paper. As shown in Fig. 8B, a DHT-treated SOD1-G93A mouse displayed a longer step length compared with a littermate control SOD1-G93A mouse at P100. Analysis of step length illustrates that DHT-implanted SOD1-G93A mice displayed a longer step length compared with control SOD1-G93A mice during disease progression (p = 0.003, Fig. 8C). Consistent with the ameliorated motor dysfunction observed in DHT-treated SOD1-G93A mice, the mean survival duration after drug treatment was increased by about 11% in DHT-treated SOD1-G93A mice (82.9±2.9 days) compared with control SOD1-G93A mice (74.8±2.2 days) (Fig. 8D). The overall lifespan of DHT-treated SOD1-G93A mice also showed a slight, but significant increase by 5% (157.9±2.9 days, n = 18), as compared to control SOD1-G93A mice (149.8±2.2 days, n = 24) (p = 0.0174; log-rank test, Fig. 8E). In summary, DHT treatment delayed motor impairment as assessed by the rota-rod, grip-strength, and foot-print analyses, and moreover extended lifespan in SOD1-G93A mice.


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 motor performances and survival in SOD1 mice.A: SOD1 mice were implanted with either a DHT-filled or an empty silastic (control) tube at P75, and their motor performances were assessed every 5 days by the rota-rod test. A mouse was placed on the rotating rod at 11 rpm, and the latency until the mouse fell from the rotating rod was recorded in seconds. DHT-treated SOD1 mice (filled square, n = 16) stayed longer on the rotating rod compared with control SOD1 mice (empty circle, n = 22). Data are mean ± SEM. p = 0.043 (2-way ANOVA). B: Hindlimbs were placed into non-toxic paints and a mouse was allowed to walk on a 50 cm- length of paper, and its continuous locomotion was recorded. Representative footprints obtained from DHT-implanted or empty tube-implanted SOD1 mice at P100 are shown. DHT-treated SOD1 mouse (top panel) showed a longer step length without a trace of dragging hindlimb compared with control SOD1 mice (bottom panel). C: Step length was quantified by dividing walking distance by the number of the steps taken within the measured walking distance. DHT-treated SOD1 mice (filled square, n = 6) showed longer step length compared with control SOD1 mice (empty circle, n = 7). p = 0.003 (paired t-test). D: DHT-treated SOD1 mice showed significantly increased survival duration after DHT administration by 11% in DHT-treated SOD1-G93A mice (82.9±2.9 days, n = 18) compared with age-matched control SOD1-G93A mice (74.8±2.2 days, n = 24). E: DHT-treated SOD1 mice showed significantly increased the overall lifespan by 8 days (filled square, 157.9±2.9 days, n = 18) compared with control SOD1 mice (empty circle, 149.8±2.2 days, n = 24). p = 0.0174 (log-rank test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351454&req=5

pone-0037258-g008: DHT improves motor performances and survival in SOD1 mice.A: SOD1 mice were implanted with either a DHT-filled or an empty silastic (control) tube at P75, and their motor performances were assessed every 5 days by the rota-rod test. A mouse was placed on the rotating rod at 11 rpm, and the latency until the mouse fell from the rotating rod was recorded in seconds. DHT-treated SOD1 mice (filled square, n = 16) stayed longer on the rotating rod compared with control SOD1 mice (empty circle, n = 22). Data are mean ± SEM. p = 0.043 (2-way ANOVA). B: Hindlimbs were placed into non-toxic paints and a mouse was allowed to walk on a 50 cm- length of paper, and its continuous locomotion was recorded. Representative footprints obtained from DHT-implanted or empty tube-implanted SOD1 mice at P100 are shown. DHT-treated SOD1 mouse (top panel) showed a longer step length without a trace of dragging hindlimb compared with control SOD1 mice (bottom panel). C: Step length was quantified by dividing walking distance by the number of the steps taken within the measured walking distance. DHT-treated SOD1 mice (filled square, n = 6) showed longer step length compared with control SOD1 mice (empty circle, n = 7). p = 0.003 (paired t-test). D: DHT-treated SOD1 mice showed significantly increased survival duration after DHT administration by 11% in DHT-treated SOD1-G93A mice (82.9±2.9 days, n = 18) compared with age-matched control SOD1-G93A mice (74.8±2.2 days, n = 24). E: DHT-treated SOD1 mice showed significantly increased the overall lifespan by 8 days (filled square, 157.9±2.9 days, n = 18) compared with control SOD1 mice (empty circle, 149.8±2.2 days, n = 24). p = 0.0174 (log-rank test).
Mentions: To determine whether the improved morphological features in DHT-treated SOD1-G93A mice would lead to functional improvement, we tested the effects of DHT treatment in motor behavior and survival of SOD1-G93A mice. In addition to the grip-strength analysis (Fig. 3B), which we previously performed in relation to muscle mass, we further employed rota-rod and footprint analyses as more global assessments of functional outcome. The rota-rod test requires an ability to balance on the rotating rod in addition to muscle strength. Although both DHT-treated and control SOD1-G93A mice showed a similar decline of motor function in the rota-rod test, the gap between two groups increased as disease progressed (Fig. 8A). For example, DHT-treated SOD1-G93A mice stayed 40% longer on the rotating rod compared to control SOD1-G93A mice at P140 (Fig. 8A, p = 0.043). To perform footprint analysis, which are used to detect impaired motor behavior [43], the paws of SOD1-G93A mice were placed into non-toxic paints and allowed to walk on a paper. As shown in Fig. 8B, a DHT-treated SOD1-G93A mouse displayed a longer step length compared with a littermate control SOD1-G93A mouse at P100. Analysis of step length illustrates that DHT-implanted SOD1-G93A mice displayed a longer step length compared with control SOD1-G93A mice during disease progression (p = 0.003, Fig. 8C). Consistent with the ameliorated motor dysfunction observed in DHT-treated SOD1-G93A mice, the mean survival duration after drug treatment was increased by about 11% in DHT-treated SOD1-G93A mice (82.9±2.9 days) compared with control SOD1-G93A mice (74.8±2.2 days) (Fig. 8D). The overall lifespan of DHT-treated SOD1-G93A mice also showed a slight, but significant increase by 5% (157.9±2.9 days, n = 18), as compared to control SOD1-G93A mice (149.8±2.2 days, n = 24) (p = 0.0174; log-rank test, Fig. 8E). In summary, DHT treatment delayed motor impairment as assessed by the rota-rod, grip-strength, and foot-print analyses, and moreover extended lifespan in SOD1-G93A mice.

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