Oral digoxin effects on exercise performance, K regulation and skeletal muscle Na ,K -ATPase in healthy humans.

We 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% , 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, [ H]-ouabain binding site content (OB-F ) was unchanged; however, bound-digoxin removal with Digibind revealed total ouabain binding (OB+F ) 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 ] were unchanged, whilst [K ] was lower (P = 0.042) and [K ] greater (P = 0.004) than in CON; with exercise (main effects), muscle OB-F 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 ] , [K ] and [K ] were each increased at fatigue (P = 0.001). During FF, in DIG (main effects), time to fatigue, [K ] , [K ] and [K ] were unchanged; with exercise (main effects), plasma [K ] , [K ] , [K ] 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. KEY 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 ([ H]-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.