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 
. The majority of ALS cases are sporadic ALS caused by unknown etiology, while about 10% of ALS cases are the inherited form of ALS, called familial ALS (fALS). Recently, mutations in TDP-43 and FUS/TLS, which are DNA/RNA-binding proteins, were found in both types of ALS 
. With a higher frequency, 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 
. 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 
Furthermore, accumulating studies suggested that mutant SOD1-mediated toxicity in non-neuronal cells such as skeletal muscle and glial cells contribute to motoneuron degeneration in ALS 
. In accordance with the current notion that ALS is a non-cell autonomous disease and involves multiple cell types, inhibiting motoneuron death through Bax knock-out is not sufficient to prevent clinical symptoms of ALS, particularly in muscle 
. Considering that muscle-related symptoms are closely related with the quality of the patient's life, targeting ALS-affected muscle may provide practical benefits to patients.
As a therapeutic intervention to reduce muscle weakness and atrophy, administration of androgens could be a potential strategy due to their roles in increasing muscle size and strength 
. Androgens have been used for anabolic therapies to treat muscle wasting caused by chronic illness and aging 
. However, it is not known whether androgen treatment can also increase muscle mass and strength in ALS patients who suffer from progressive muscle atrophy and associated motor defects. It is interesting to note that ALS patients show a lower level of free testosterone, which is a bioavailable form of androgen, compared with a non-ALS control group 
. Since a low level of testosterone is associated with reduced muscle mass and strength 
, it is possible that reduced androgen observed in ALS patients may contribute to muscle atrophy and weakness. Taken together, reduced androgen level may play a role in reducing the size and strength of skeletal muscle in ALS, and therefore androgen treatment might be one of the therapeutic approaches to alleviate muscle symptoms.
In addition to anabolic effects on muscle, androgen may directly benefit motoneurons through the highly expressed androgen receptors (ARs) in the ventral horn of the spinal cord 
. The neuroprotective effects of androgens in promoting neuronal survival and neurite outgrowth have been found in the spinal motoneurons, and extensively in sexually dimorphic motoneurons such as the spinal nucleus of the bulbocavernosus 
. Particularly, androgens enhance regeneration of the sciatic nerve after nerve crush by increasing the rate of nerve growth towards its target hindlimb muscles 
. Given that progressive motoneuron death and “dying-back” axonal retraction are the manifested pathology in ALS 
, androgens may delay disease progression through its neuroprotective effects.
To examine a potential therapeutic effect of androgens in ALS, we administrated 5α-dihydrotestosterone (DHT), a metabolite of testosterone, to SOD1-G93A mice. The SOD1- G93A transgenic mouse is one of the extensively used animal models of ALS, which replicates pathological courses of ALS patients. SOD1-G93A transgenic mice demonstrate muscle atrophy and neuromuscular junction denervation from ~50 days of age, ventral axon loss from ~80 days of age, and motoneuron death from ~100 days of age in a “dying-back” fashion 
, and typically die at ~140 days of age 
. A silicon tubing containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age to mimic the time point when patients may receive treatments. In the present study, we found that DHT treatment ameliorates morphological defects in skeletal muscle, nerves, and motoneurons in SOD1-G93A mice. The morphological improvement was accompanied by enhanced motor performance and slightly increased survival duration.