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 the newly administered K⁺ tracer in resting rats was taken up by extrarenal tissues rather than excreted by the kidney within 5 h 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⁺].