title: Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice.
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.
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Yoo
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Ko
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D013196:Dihydrotestosterone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009048:Motor Skills / Q000187:drug effects; D009124:Muscle Proteins / Q000235:genetics; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000188:drug therapy / Q000473:pathology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D000728:Androgens; C513121:IGF2 protein, mouse; D009124:Muscle Proteins; D018696:Neuroprotective Agents; D000070584:Tripartite Motif Proteins; C519530:insulin-like growth factor-1, mouse; D013196:Dihydrotestosterone; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases