Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice

• Published in: PloS one 2012-05, Vol.7 (5), p.e37258
• Main Authors: Yoo, Young-Eun, Ko, Chien-Ping
• Format: Article
• Language: English
• Subjects: Age; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Analysis; Androgens; Androgens - metabolism; Animals; Atrophy; Axons; Axons - drug effects; Axons - pathology; Biology; Body weight; Body Weight - drug effects; Cell culture; Crystals; Degeneration; Denervation; Dihydrotestosterone; Dihydrotestosterone - therapeutic use; Disease Models, Animal; Energy; Gait; Gene Expression - drug effects; Homeostasis; Humans; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor II - genetics; Laboratory animals; Life span; Male; Medicine; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Morphology; Motor neurons; Motor Neurons - drug effects; Motor Neurons - pathology; Motor Neurons - physiology; Motor Skills - drug effects; Motor task performance; Muscle Proteins - genetics; Muscle Strength - drug effects; Muscle, Skeletal - drug effects; Muscle, Skeletal - innervation; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscles; Muscular Atrophy - drug therapy; Muscular Atrophy - pathology; Musculoskeletal system; Mutation; Neurobiology; Neuromuscular Junction - drug effects; Neuromuscular Junction - pathology; Neurons; Neuroprotection; Neuroprotective Agents - therapeutic use; Neurosciences; Physiological aspects; Quality of life; Retrograde transport; Rodents; Sex hormones; Skeletal muscle; Spinal cord; Superoxide dismutase; Superoxide Dismutase - genetics; Testosterone; Transgenic animals; Trends; Tripartite Motif Proteins; Ubiquitin-Protein Ligases - genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0037258

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.