Amyotrophic lateral sclerosis is the most common form of motor neuron disease in adult patients and characterized by progressive paralysis. The wobbler mouse (phenotype WR, genotype wr/wr) is an established animal model of human motor neuron disease and is characterized by a large variety of cellular abnormalities including muscular atrophy. In analogy to recent proteomic studies of cerebrospinal fluid and spinal cord, we have used here fluorescence difference in-gel electrophoresis to analyze global changes in the skeletal muscle proteome from WR versus normal mice. Relative concentrations of 21 proteins were found to be increased and 3 proteins were decreased. Mass spectrometric analysis identified these proteins to be associated with key metabolic pathways, the contractile apparatus, intermediate filaments and the cellular stress response. Drastically increased levels of the glycolytic enzyme glyceraldehyde- 3-phosphate dehydrogenase were confirmed by immunoblotting and this finding agrees with the idea of an oxidative-to-glycolytic shift in disease-related muscular atrophy. The establishment of novel disease-specific biomarkers of motor neuron disease might be helpful in the design of improved diagnostic tools and the identification of novel therapeutic targets.