Quantitative Analysis of Skeletal Muscle Contributions to ECF K ⁺ Homeostasis

There is a division of labor between the kidney and extrarenal tissues in extracellular fluid (ECF) K ⁺ homeostasis. The kidney modulates K ⁺ excretion to match K ⁺ intake, maintaining daily K ⁺ balance, whereas extrarenal tissues, primarily skeletal muscle, regulate K ⁺ shifts between the ECF and intracellular fluid (ICF). Our recent stable isotope-based modeling study revealed that approximately 98% of newly administered K ⁺ tracer in resting rats was taken up by extrarenal tissues rather than excreted by the kidney within 5 hours of administration, indicating that K ⁺ exchange between the ECF and ICF pools occurs extremely rapidly. Emerging evidence also suggests that K ⁺ influx into skeletal muscle varies linearly with physiological ECF K ⁺ concentration ([K ⁺ ]). These characteristics, combined with its large ICF pool, give skeletal muscle both a high capacity for buffering ECF K ⁺ and strong control efficiency in modulating K ⁺ movements into and out of the ICF. The large K ⁺ fluxes into skeletal muscleand their dependence on ECF [K ⁺ ]position skeletal muscle as a key regulator of ECF K ⁺ homeostasis, alongside insulin, during acute dietary K ⁺ intake and in the maintenance of postabsorptive ECF [K ⁺ ]. Furthermore, these features provide a mechanism by which insulin’s actions on K ⁺ fluxes are attenuated to prevent hypokalemia when a low-K ⁺ diet is consumed. In this mini‑review, we present quantitative analyses of skeletal muscle function in both acute and long-term K ⁺ homeostasis under conditions of altered K ⁺ intake, highlighting its role as a sensor, reservoir, and regulator of ECF [K ⁺ ].