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 alpha(2)-isoform leads to the specific shift of K(+) from muscle ICF to ECF. The skeletal muscle response is isoform and muscle specific: alpha(2) and beta(2), not alpha(1) and beta(1), levels are depressed, and fast glycolytic muscles lose >90% alpha(2), 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.