Coordinate adaptations of skeletal muscle and kidney to adjust extracellular [K+] during K+ deficient diet in mice.

Extracellular fluid (ECF) [K+] is maintained by adaptations of kidney and skeletal muscle, responses heretofore studied separately. We aimed to determine how these organ systems work in concert to preserve ECF [K+] in male C57BL/6J mice fed a K+ deficient diet (0K) versus 1% K+ diet (1K) for 10 days (n=5-6/group). During 0K feeding, plasma [K+] fell from 4.5 to 2 mM; hindlimb muscle (gastrocnemius and soleus) lost 28 mM K+ (from 115 ± 2 to 87 ± 2 mM) and gained 27 mM Na+ (from 27 ± 0.4 to 54 ± 2 mM). Doubling of muscle tissue [Na+] was not associated with inflammation, cytokine production or hypertension as reported by others. Muscle transporters' adaptations in 0K vs. 1K fed mice, assessed by immunoblot, included decreased sodium pump a2-b2 subunits, decreased K+- Cl-- cotransporter isoform 3, and increased phosphorylated (p) Na+-K+-2 Cl- cotransporter isoform 1 (NKCC1p), Ste20/SPS-1 related proline-alanine rich kinase (SPAKp) and oxidative stress responsive kinase 1 (OSR1p) consistent with intracellular fluid (ICF) K+ loss and Na+ gain. Renal transporters' adaptations, effecting a 98% reduction in K+ excretion, included 2-3-fold increased phosphorylated Na+-Cl- cotransporter (NCCp), SPAKp and OSR1p abundance, limiting Na+ delivery to epithelial Na+ channels where Na+ reabsorption drives K+ secretion; renal K sensor Kir 4.1 abundance fell 25%. Mass balance estimations indicate that over 10 days of 0K feeding, mice lose ~48 mmol K+ into the urine and muscle shifts ~47 mmol K+ from ICF to ECF, illustrating the importance of the concerted responses during K+ deficiency.