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

Young-Eun Yoo,Chien-Ping Ko,Lin Mei

doi:10.1371/journal.pone.0037258

Young-Eun Yoo, Chien-Ping Ko + Show 1 more

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https://doi.org/10.1371/journal.pone.0037258

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Journal: PloS one	Publication Date: May 14, 2012
Citations: 111	License type: CC BY 4.0

Affiliation: University of Southern California

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease characterized by a progressive loss of motoneurons in the brain and spinal cord
By using quantitative RT-PCR, we found that there was a trend that DHT treatment decreased the expression of Muscle ring finger (MuRF)-1 by 43.9% compared with control superoxide dismutase 1 (SOD1)-G93A mice (p = 0.198, Fig. 4B), which implies that molecular pathway that triggers muscle atrophy might be attenuated by DHT treatment
The present study demonstrated that DHT alleviated the pathological symptoms found in the skeletal muscle of SOD1G93A mice, which includes muscle atrophy and weakness

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease characterized by a progressive loss of motoneurons in the brain and spinal cord. The clinical symptoms of ALS include skeletal muscle weakness, atrophy and paralysis, which eventually lead to fatal respiratory failure within 2–5 years from the disease onset [1]. Mutations in the human superoxide dismutase 1 (SOD1) gene are found in about 20% of fALS patients, and inserting these mutated human SOD1 genes into rodents have generated ALS animal models [3]. SOD1 mutations induce a gain of toxic function instead of a loss of enzymatic function, which converts reactive superoxide into hydrogen peroxide and water to reduce oxidative stress [4]

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