Oral digoxin effects on exercise performance, K+ regulation and skeletal muscle Na+,K+‐ATPase in healthy humans
Authors: Sostaric Simon , Petersen Aaron C. , Goodman Craig A. , Gong Xiaofei , Aw Tai‐Juan , Brown Malcolm J. , Garnham Andrew , Steward Collene H. , Murphy Kate T. , Carey Kate A. , Leppik James , Fraser Steve F. , Cameron‐Smith David , Krum Henry , Snow Rodney J. , McKenna Michael J. 
Published: July 2022

AbstractWe investigated whether digoxin lowered muscle Na+,K+‐ATPase (NKA), impaired muscle performance and exacerbated exercise K+ disturbances. Ten healthy adults ingested digoxin (0.25 mg; DIG) or placebo (CON) for 14 days and performed quadriceps strength and fatiguability, finger flexion (FF, 105%peak‐workrate, 3 × 1 min, fourth bout to fatigue) and leg cycling (LC, 10 min at 33% and 67% , 90% to fatigue) trials using a double‐blind, crossover, randomised, counter‐balanced design. Arterial (a) and antecubital venous (v) blood was sampled (FF, LC) and muscle biopsied (LC, rest, 67% , fatigue, 3 h after exercise). In DIG, in resting muscle, [3H]‐ouabain binding site content (OB‐Fab) was unchanged; however, bound‐digoxin removal with Digibind revealed total ouabain binding (OB+Fab) increased (8.2%, P = 0.047), indicating 7.6% NKA–digoxin occupancy. Quadriceps muscle strength declined in DIG (−4.3%, P = 0.010) but fatiguability was unchanged. During LC, in DIG (main effects), time to fatigue and [K+]a were unchanged, whilst [K+]v was lower (P = 0.042) and [K+]a‐v greater (P = 0.004) than in CON; with exercise (main effects), muscle OB‐Fab was increased at 67% (per wet‐weight, P = 0.005; per protein P = 0.001) and at fatigue (per protein, P = 0.003), whilst [K+]a, [K+]v and [K+]a‐v were each increased at fatigue (P = 0.001). During FF, in DIG (main effects), time to fatigue, [K+]a, [K+]v and [K+]a‐v were unchanged; with exercise (main effects), plasma [K+]a, [K+]v, [K+]a‐v and muscle K+ efflux were all increased at fatigue (P = 0.001). Thus, muscle strength declined, but functional muscle NKA content was preserved during DIG, despite elevated plasma digoxin and muscle NKA–digoxin occupancy, with K+ disturbances and fatiguability unchanged.
imageKey points
The Na+,K+‐ATPase (NKA) is vital in regulating skeletal muscle extracellular potassium concentration ([K+]), excitability and plasma [K+] and thereby also in modulating fatigue during intense contractions.

NKA is inhibited by digoxin, which in cardiac patients lowers muscle functional NKA content ([3H]‐ouabain binding) and exacerbates K+ disturbances during exercise.
In healthy adults, we found that digoxin at clinical levels surprisingly did not reduce functional muscle NKA content, whilst digoxin removal by Digibind antibody revealed an ∼8% increased muscle total NKA content.
Accordingly, digoxin did not exacerbate arterial plasma [K+] disturbances or worsen fatigue during intense exercise, although quadriceps muscle strength was reduced.
Thus, digoxin treatment in healthy participants elevated serum digoxin, but muscle functional NKA content was preserved, whilst K+ disturbances and fatigue with intense exercise were unchanged. This resilience to digoxin NKA inhibition is consistent with the importance of NKA in preserving K+ regulation and muscle function.