This study shows that aged tg mice expressing wild-type-, G37R-, and G93A-human SOD1 gene variants only in skeletal muscle develop a fatal ALS-like disease phenotype involving prominent skeletal muscle and spinal cord pathology, suggesting a skeletal muscle disease triggered, MN non-autonomous degeneration in ALS driven by DNA damage and retrograde neurodegeneration. The gene discussed is SOD1; the disease is amyotrophic lateral sclerosis.