Model: The α1 and α2 isoforms of the Na,K-ATPase in skeletal muscles operate over different ranges of extracellular K⁺ concentrations. During repetitive action potential activity, extracellular K⁺ increases up to 10–12 mM in the muscle interstitial spaces and can reach tens of millimolar in the T-tubules. Increased K⁺ rapidly stimulates the activity of both isoforms by increasing the occupancy of the extracellular K⁺ sites of the enzyme. The α1 isoform, localized in the outer sarcolemma, operates above its K_1/2,K (1–2 mM) at resting extracellular [K⁺] (4 mM), and plays a major role in setting resting ion gradients and the resting potential. The α2 isoform is the sole Na,K-ATPase in the T-tubules. It operates below its maximum activity in resting muscles, but its activity can be rapidly increased during membrane excitation to meet the increased demands of working muscle for Na/K transport. The cartoon emphasizes the spatial segregation and different K_1/2,K constants of α1 and α2 isoforms, which match the range of [K⁺] expected at rest and during activity. The model also suggests that a small fraction of the K⁺ can diffuse out of the tubular system through the tubule openings. For simplicity, only voltage-dependent sodium and potassium channels (Nav1.4 and Kv1.4/Kv3.4) are indicated. Kir channels are also expected to contribute to the recovery of K⁺, because the electromotive force for K⁺ is inward above 4 mM [K⁺]_o.