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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 the expression of insulin-like growth factor -1 and -2, while decreases MuRF-1 expression.A: The TA muscles were collected from DHT-treated SOD1 and control SOD1 mice at P120 to check the expression of insulin-like growth factor (IGF) -1 and IGF-2 through quantitative RT-PCR. DHT-treated SOD1 mice showed increased expression of IGF-1 and IGF-2, by approximately 4-fold (p = 0.0261), and 2-fold (p = 0.015), respectively, compared with control SOD1 mice. *p<0.05. B: By using quantitative RT-PCR, we found that DHT-treated SOD1 mice showed a trend of decreased expression of MuRF-1 by 44% compared with control SOD1 mice (p = 0.198).
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pone-0037258-g004: DHT increases the expression of insulin-like growth factor -1 and -2, while decreases MuRF-1 expression.A: The TA muscles were collected from DHT-treated SOD1 and control SOD1 mice at P120 to check the expression of insulin-like growth factor (IGF) -1 and IGF-2 through quantitative RT-PCR. DHT-treated SOD1 mice showed increased expression of IGF-1 and IGF-2, by approximately 4-fold (p = 0.0261), and 2-fold (p = 0.015), respectively, compared with control SOD1 mice. *p<0.05. B: By using quantitative RT-PCR, we found that DHT-treated SOD1 mice showed a trend of decreased expression of MuRF-1 by 44% compared with control SOD1 mice (p = 0.198).

Mentions: Increased skeletal muscle mass through androgens is known to be mediated by insulin-like growth factor (IGF-1), which induces myoblast proliferation, differentiation, and hypertrophy [33], [34], [35], [36]. To examine whether DHT increases IGF-1 expression in skeletal muscle of SOD1-G93A mice, we performed quantitative RT-PCR. As shown in Fig. 4A, DHT treatment increased the expression of IGF-1 by about 4-fold (p = 0.0261) in the TA muscle compared with control SOD1-G93A mice at P120. Similarly, the expression level of IGF-2, which plays a similar role in muscle to IGF-1 [37], [38], was also increased by about 2-fold (p = 0.015) in DHT-treated SOD1-G93A mice compared with control SOD1-G93A mice (Fig. 4A).


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 the expression of insulin-like growth factor -1 and -2, while decreases MuRF-1 expression.A: The TA muscles were collected from DHT-treated SOD1 and control SOD1 mice at P120 to check the expression of insulin-like growth factor (IGF) -1 and IGF-2 through quantitative RT-PCR. DHT-treated SOD1 mice showed increased expression of IGF-1 and IGF-2, by approximately 4-fold (p = 0.0261), and 2-fold (p = 0.015), respectively, compared with control SOD1 mice. *p<0.05. B: By using quantitative RT-PCR, we found that DHT-treated SOD1 mice showed a trend of decreased expression of MuRF-1 by 44% compared with control SOD1 mice (p = 0.198).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3351454&req=5

pone-0037258-g004: DHT increases the expression of insulin-like growth factor -1 and -2, while decreases MuRF-1 expression.A: The TA muscles were collected from DHT-treated SOD1 and control SOD1 mice at P120 to check the expression of insulin-like growth factor (IGF) -1 and IGF-2 through quantitative RT-PCR. DHT-treated SOD1 mice showed increased expression of IGF-1 and IGF-2, by approximately 4-fold (p = 0.0261), and 2-fold (p = 0.015), respectively, compared with control SOD1 mice. *p<0.05. B: By using quantitative RT-PCR, we found that DHT-treated SOD1 mice showed a trend of decreased expression of MuRF-1 by 44% compared with control SOD1 mice (p = 0.198).
Mentions: Increased skeletal muscle mass through androgens is known to be mediated by insulin-like growth factor (IGF-1), which induces myoblast proliferation, differentiation, and hypertrophy [33], [34], [35], [36]. To examine whether DHT increases IGF-1 expression in skeletal muscle of SOD1-G93A mice, we performed quantitative RT-PCR. As shown in Fig. 4A, DHT treatment increased the expression of IGF-1 by about 4-fold (p = 0.0261) in the TA muscle compared with control SOD1-G93A mice at P120. Similarly, the expression level of IGF-2, which plays a similar role in muscle to IGF-1 [37], [38], was also increased by about 2-fold (p = 0.015) in DHT-treated SOD1-G93A mice compared with control SOD1-G93A mice (Fig. 4A).

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