High frequency stimulation of skeletal muscle has long been associated with ionic perturbations, resulting in the loss of membrane excitability, which may prevent action potential propagation and result in skeletal muscle fatigue. Associated with intense skeletal muscle contractions are large changes in muscle metabolites. However, the role of metabolites in the loss of muscle excitability is not clear. The metabolic state of isolated rat extensor digitorum longus muscles at 30°C was manipulated by decreasing energy expenditure and thereby allowed investigation of the effects of energy conservation on skeletal muscle excitability. Muscle ATP utilization was reduced using a combination of the cross-bridge cycling blocker, N-benzyl-p-toluene sulphonamide (BTS), and the SR Ca²⁺ release channel blocker, Na-dantrolene, which reduce activity of the myosin ATPase and SR Ca²⁺-ATPase. Compared to control muscles, the resting metabolites, ATP, PCr, Cr, and lactate as well as the resting muscle excitability, as measured by M-waves, were unaffected by treatment with BTS + dantrolene. Following 20 or 30s of continuous 60Hz stimulation, BTS + dantrolene treated muscles showed a 25% lower ATP utilization compared to control muscles. Furthermore, the ability of muscles to maintain excitability during high frequency stimulation was significantly improved in BTS + dantrolene treated muscles, indicating a strong link between metabolites, energetic state and the excitability of the muscle.