The innate immune system requires input from a myriad of tissues and cell types to adequately prepare, locate, and neutralize infections. Skeletal muscle's widespread distribution throughout the body and its potent ability to secrete cytokines makes it a vital signaling organ to alert the immune system during both localized and systemic injuries and illnesses. This dissertation first deciphers the crosstalk between skeletal muscle myocytes and macrophages during acute lung injury, reporting the macrophage-derived cytokine, tumor necrosis factor [alpha], to be necessary for eliciting the full potential of the skeletal muscle inflammatory milieu. Next, the total contribution of skeletal muscle mediators is quantified using muscle specific knockouts for toll-like receptor 4, interleukin-6, and C-C motif chemokine ligand 2. These novel mouse strains allow for targeted ablation of the receptor and effector molecules involved in endotoxemia specifically in myocytes, providing insight on the proportion of inflammatory cytokines derived from these muscle cells. Finally, to improve skeletal muscle and exercise research, a novel, open-source mouse exercise wheel is presented that allows for controllable and trackable experimentation. This device improves upon existing methods by allowing researchers to limit animals based on time- and distance- milestones. Together, these data provide a comprehensive examination spanning from molecular signaling to animal modeling of the mechanisms and magnitude to which skeletal muscle regulates immune homeostasis.