Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease in which patients become gradually paralyzed and ultimately die from respiratory failure. While ALS is classified as a motor neuron disease, in recent years there has been increasing evidence of the involvement of additional cell types, including skeletal muscle. However, the role of skeletal muscle in the ALS disease process is largely unknown. To investigate, we differentiated ALS patient induced pluripotent stem cells (iPSCs) into skeletal myocytes for in vitro disease modeling. First, we used iPSCs from ALS patients with the C9ORF72 hexanucleotide repeat expansion, the most common gene mutation to cause ALS. We found that these iPSC-derived myocytes showed hallmark signs of the mutation including repeat RNA foci and dipeptide repeat proteins. The cells also had changes in mitochondrial gene expression and a susceptibility to oxidative stress. Next, we used RNA sequencing to compare gene expression across many ALS backgrounds including SOD1, TARDBP, and sporadic patients. We found that four genes (BET1L, DCX, GPC3, HNRNPK) were commonly down-regulated in ALS myocytes compared to controls and BET1L in particular was also decreased in a rat model of familial ALS (SOD1G93A transgenic). We found that the Bet1L protein was strongly expressed at the neuromuscular junction (NMJ) and decreased with disease progression in the SOD1G93A rats. Therefore, Bet1L may be a promising therapeutic target for ALS patients of many genetic backgrounds. Finally, we developed in vitro co-culture systems of iPSC-derived skeletal myocytes and motor neurons to study ALS NMJ pathology. We found that treating healthy motor neurons with conditioned media from ALS myocytes causes morphological changes and increased apoptosis. Together these results support the hypothesis that ALS skeletal muscle contains cellular pathology independent of denervation and may even play an active role in the disease process by influencing NMJ degeneration and motor neuron survival.