Skeletal muscle makes up ~50% of body weight in horses, with protein being the largest nonwater component. Muscle mass is largely determined by the balance of rates of muscle protein synthesis and breakdown. In an athletic species such as the horse, where muscle mass has been associated with performance, there is a need to understand how the underlying signaling pathways are regulated. In horses, similar to other species, activation of the downstream factors (4E-BP1, rpS6, S6K1) in the mechanistic target of rapamycin (mTOR) signaling pathway regulating protein synthesis is increased following feeding and insulin administration. The activation in response to feeding decreases with age in growing horses, with the muscle of yearlings being more responsive to feeding than that of 2 year olds. When horses are in an unfed state, there is no effect of age on the activation of mTOR signaling factors, either during growth or when comparing mature to old (> 20 yr old) horses. When comparing 2 populations of old horses: those that are relatively healthy and those with pituitary pars intermedia dysfunction, a condition that has been associated with a loss of muscle mass and insulin resistance, there were no differences between groups in the muscle activation or abundance of any of the mTOR signaling factors, myostatin (a factor related to muscle loss), or factors associated with the protein degradation signaling pathways (FoxO, atrogin-1, MuRF1), in response to either feeding or insulin infusion. Changes that occur in the muscle signaling pathways of old horses is an area where additional research is needed. In a dexamethasone-induced model of insulin resistance, where glucose uptake in response to insulin infusion was decreased by ~75%, there were profound decreases in the activation of mTOR signaling factors. These findings indicate that, in addition to being a risk factor for the development of laminitis and equine metabolic syndrome, insulin resistance may also impair the ability of the horse to maintain muscle mass, although additional research in other equine models of insulin resistance is needed. Understanding the factors that regulate the signaling pathways of muscle protein synthesis and breakdown will allow the development of management and feeding strategies to promote muscle mass accretion and maintenance throughout the lifespan.