Skeletal muscle regulates extracellular potassium

Abstract

Maintaining extracellular fluid (ECF) K+ concentration ([K+]) within a narrow range is accomplished by the concerted responses of the kidney, which matches K+ excretion to K+ intake, and skeletal muscle, the main intracellular fluid (ICF) store of K+, which can rapidly buffer ECF [K+]. In both systems, homologous P-type ATPase isoforms are key effectors of this homeostasis. During dietary K+ deprivation, these P-type ATPases are regulated in opposite directions: increased abundance of the H,K-ATPase “colonic” isoform in the renal collecting duct drives active K+ conservation while decreased abundance of the plasma membrane Na,K-ATPase α2-isoform leads to the specific shift of K+ from muscle ICF to ECF. The skeletal muscle response is isoform and muscle specific: α2 and β2, not α1 and β1, levels are depressed, and fast glycolytic muscles lose >90% α2, whereas slow oxidative muscles lose ∼50%; however, both muscle types have the same fall in cellular [K+]. To understand the physiological impact, we developed the “K+ clamp” to assess insulin-stimulated cellular K+ uptake in vivo in the conscious rat by measuring the exogenous K+ infusion rate needed to maintain constant plasma [K+] during insulin infusion. Using the K+ clamp, we established that K+deprivation leads to near-complete insulin resistance of cellular K+ uptake and that this insulin resistance can occur before any decrease in plasma [K+] or muscle Na+ pump expression. These studies establish the advantage of combining molecular analyses of P-type ATPase expression with in vivo analyses of cellular K+ uptake and excretion to determine mechanisms in models of disrupted K+ homeostasis.