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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 ameliorates denervation at neuromuscular junctions SOD1 mice.SOD1/YFP double transgenic mice expressing yellow fluorescence protein (YFP) in all motor nerves were implanted with either a DHT-filled or an empty silastic tube, or orchidectomized at P75, and the TA muscle and the diaphragm (DIA) muscle were collected at P120, and stained with anti-α-bungarotoxin to label post-synaptic acetylcholine receptor (AChR) clusters. A: When a pre-synaptic nerve terminal (in green) fully overlaps with the post-synaptic AChR clusters (in red), the neuromuscular junction (NMJ) is defined as a “fully innervated NMJ” (d). However, if a nerve terminal is partially overlapped with AChR, or is completely absent, leaving only AChR, the NMJ is defined as a “partially innervated NMJ” (e) or a “denervated NMJ” (f), respectively. DHT-treated SOD1/YFP mice (b) showed improved NMJ innervation in the TA muscle compared with control SOD1/YFP mice (a). However, orchidectomy in SOD1/YFP mice aggravated denervation at NMJs (c). B: Quantification of NMJs at P120 in the TA muscle of DHT-treated, control, and orchidectomized SOD1/YFP mice is shown. Compared to control SOD1/YFP mice, which showed 22.3±5.7% of fully innervated NMJs, DHT-treated SOD1/YFP mice showed 47.3±14.1% of fully innervated NMJs. Orchidectomized SOD1/YFP mice showed only 9.6±3.4% of fully innervated NMJs. C: Quantification of NMJs at P120 in the DIA muscle of DHT-treated, and control SOD1/YFP mice is shown. Compared to SOD1/YFP mice, which showed 65.2±5.6% of fully innervated NMJs, DHT-treated SOD1/YFP mice showed 81.0±5.5% of fully innervated NMJs. Data are mean ± SEM. *p<0.05.
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pone-0037258-g005: DHT ameliorates denervation at neuromuscular junctions SOD1 mice.SOD1/YFP double transgenic mice expressing yellow fluorescence protein (YFP) in all motor nerves were implanted with either a DHT-filled or an empty silastic tube, or orchidectomized at P75, and the TA muscle and the diaphragm (DIA) muscle were collected at P120, and stained with anti-α-bungarotoxin to label post-synaptic acetylcholine receptor (AChR) clusters. A: When a pre-synaptic nerve terminal (in green) fully overlaps with the post-synaptic AChR clusters (in red), the neuromuscular junction (NMJ) is defined as a “fully innervated NMJ” (d). However, if a nerve terminal is partially overlapped with AChR, or is completely absent, leaving only AChR, the NMJ is defined as a “partially innervated NMJ” (e) or a “denervated NMJ” (f), respectively. DHT-treated SOD1/YFP mice (b) showed improved NMJ innervation in the TA muscle compared with control SOD1/YFP mice (a). However, orchidectomy in SOD1/YFP mice aggravated denervation at NMJs (c). B: Quantification of NMJs at P120 in the TA muscle of DHT-treated, control, and orchidectomized SOD1/YFP mice is shown. Compared to control SOD1/YFP mice, which showed 22.3±5.7% of fully innervated NMJs, DHT-treated SOD1/YFP mice showed 47.3±14.1% of fully innervated NMJs. Orchidectomized SOD1/YFP mice showed only 9.6±3.4% of fully innervated NMJs. C: Quantification of NMJs at P120 in the DIA muscle of DHT-treated, and control SOD1/YFP mice is shown. Compared to SOD1/YFP mice, which showed 65.2±5.6% of fully innervated NMJs, DHT-treated SOD1/YFP mice showed 81.0±5.5% of fully innervated NMJs. Data are mean ± SEM. *p<0.05.

Mentions: Together with muscular atrophy, denervation at the NMJs is a prominent symptom found in skeletal muscle of ALS [19], [29]. To visualize NMJs, we used double transgenic mice SOD1-G93A/YFP, which express fluorescent protein in all motor nerves. As shown in Fig. 5A and B, SOD1-G93A/YFP mice showed a 77% denervated or partially innervated NMJs in TA muscle at P120. DHT treatment decreased the denervated NMJs by 56% in the TA muscle, and increased the fully innervated NMJs by 2-fold (p = 0.02, p = 0.049, respectively, Fig. 5Ab and B). Conversely, decreasing androgen concentration through castration showed about 70% less fully innervated NMJs in the TA muscle in orchidectomized SOD1-G93A/YFP mice compared with control SOD1-G93A/YFP mice (p = 0.058, Fig. 5Ac, and B). We further examined denervation in the diaphragm muscle (DIA) that causes fatal respiratory failures in ALS patients. As shown in Fig. 5C, DHT-treated SOD1-G93A/YFP mice exhibited a 24% increase in fully innervated NMJs, and a 64% decrease in denervated NMJs compared with control SOD1-G93A/YFP mice (p = 0.0039, p = 0.014, respectively). Taken together, DHT treatment ameliorates NMJ denervation in SOD1-G93A mice, which may contribute to improved muscle phenotype and motor function.


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 ameliorates denervation at neuromuscular junctions SOD1 mice.SOD1/YFP double transgenic mice expressing yellow fluorescence protein (YFP) in all motor nerves were implanted with either a DHT-filled or an empty silastic tube, or orchidectomized at P75, and the TA muscle and the diaphragm (DIA) muscle were collected at P120, and stained with anti-α-bungarotoxin to label post-synaptic acetylcholine receptor (AChR) clusters. A: When a pre-synaptic nerve terminal (in green) fully overlaps with the post-synaptic AChR clusters (in red), the neuromuscular junction (NMJ) is defined as a “fully innervated NMJ” (d). However, if a nerve terminal is partially overlapped with AChR, or is completely absent, leaving only AChR, the NMJ is defined as a “partially innervated NMJ” (e) or a “denervated NMJ” (f), respectively. DHT-treated SOD1/YFP mice (b) showed improved NMJ innervation in the TA muscle compared with control SOD1/YFP mice (a). However, orchidectomy in SOD1/YFP mice aggravated denervation at NMJs (c). B: Quantification of NMJs at P120 in the TA muscle of DHT-treated, control, and orchidectomized SOD1/YFP mice is shown. Compared to control SOD1/YFP mice, which showed 22.3±5.7% of fully innervated NMJs, DHT-treated SOD1/YFP mice showed 47.3±14.1% of fully innervated NMJs. Orchidectomized SOD1/YFP mice showed only 9.6±3.4% of fully innervated NMJs. C: Quantification of NMJs at P120 in the DIA muscle of DHT-treated, and control SOD1/YFP mice is shown. Compared to SOD1/YFP mice, which showed 65.2±5.6% of fully innervated NMJs, DHT-treated SOD1/YFP mice showed 81.0±5.5% of fully innervated NMJs. Data are mean ± SEM. *p<0.05.
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Related In: Results  -  Collection

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pone-0037258-g005: DHT ameliorates denervation at neuromuscular junctions SOD1 mice.SOD1/YFP double transgenic mice expressing yellow fluorescence protein (YFP) in all motor nerves were implanted with either a DHT-filled or an empty silastic tube, or orchidectomized at P75, and the TA muscle and the diaphragm (DIA) muscle were collected at P120, and stained with anti-α-bungarotoxin to label post-synaptic acetylcholine receptor (AChR) clusters. A: When a pre-synaptic nerve terminal (in green) fully overlaps with the post-synaptic AChR clusters (in red), the neuromuscular junction (NMJ) is defined as a “fully innervated NMJ” (d). However, if a nerve terminal is partially overlapped with AChR, or is completely absent, leaving only AChR, the NMJ is defined as a “partially innervated NMJ” (e) or a “denervated NMJ” (f), respectively. DHT-treated SOD1/YFP mice (b) showed improved NMJ innervation in the TA muscle compared with control SOD1/YFP mice (a). However, orchidectomy in SOD1/YFP mice aggravated denervation at NMJs (c). B: Quantification of NMJs at P120 in the TA muscle of DHT-treated, control, and orchidectomized SOD1/YFP mice is shown. Compared to control SOD1/YFP mice, which showed 22.3±5.7% of fully innervated NMJs, DHT-treated SOD1/YFP mice showed 47.3±14.1% of fully innervated NMJs. Orchidectomized SOD1/YFP mice showed only 9.6±3.4% of fully innervated NMJs. C: Quantification of NMJs at P120 in the DIA muscle of DHT-treated, and control SOD1/YFP mice is shown. Compared to SOD1/YFP mice, which showed 65.2±5.6% of fully innervated NMJs, DHT-treated SOD1/YFP mice showed 81.0±5.5% of fully innervated NMJs. Data are mean ± SEM. *p<0.05.
Mentions: Together with muscular atrophy, denervation at the NMJs is a prominent symptom found in skeletal muscle of ALS [19], [29]. To visualize NMJs, we used double transgenic mice SOD1-G93A/YFP, which express fluorescent protein in all motor nerves. As shown in Fig. 5A and B, SOD1-G93A/YFP mice showed a 77% denervated or partially innervated NMJs in TA muscle at P120. DHT treatment decreased the denervated NMJs by 56% in the TA muscle, and increased the fully innervated NMJs by 2-fold (p = 0.02, p = 0.049, respectively, Fig. 5Ab and B). Conversely, decreasing androgen concentration through castration showed about 70% less fully innervated NMJs in the TA muscle in orchidectomized SOD1-G93A/YFP mice compared with control SOD1-G93A/YFP mice (p = 0.058, Fig. 5Ac, and B). We further examined denervation in the diaphragm muscle (DIA) that causes fatal respiratory failures in ALS patients. As shown in Fig. 5C, DHT-treated SOD1-G93A/YFP mice exhibited a 24% increase in fully innervated NMJs, and a 64% decrease in denervated NMJs compared with control SOD1-G93A/YFP mice (p = 0.0039, p = 0.014, respectively). Taken together, DHT treatment ameliorates NMJ denervation in SOD1-G93A mice, which may contribute to improved muscle phenotype and motor function.

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