MyoD and myogenin are myogenic transcription factors preferentially expressed in adult fast and slow muscles, respectively. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which motor neuron loss is accompanied by muscle denervation and paralysis. Studies suggest that muscle phenotype may influence ALS disease progression. Here we demonstrate that myogenin gene transfer into muscle supports spinal cord motor neuron survival and muscle endplate innervation in the G93A SOD1 fALS mice. On the other hand, MyoD gene transfer decreases survival and enhances motor neuron degeneration and muscle denervation. Although an increase in motor neuron count is associated with increased succinic dehydrogenase staining in the muscle, muscle overexpression of PGC-1α does not improve survival or motor function. Our study suggests that postnatal muscle modification influences disease progression and demonstrates that the muscle expression of myogenic and metabolic regulators differentially impacts neuropathology associated with disease progression in the G93A SOD1 fALS mouse model.