Oral digoxin effects on exercise performance, K(+) regulation and skeletal muscle Na(+),K(+)‐ATPase in healthy humans

ABSTRACT: 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%(peak‐workrate), 3 × 1 min, fourth bout to fatigue) and leg cycling (LC, 10 min at 33% [Formula: see text] and 67% [Formula: see text] , 90% [Formula: see text] 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% [Formula: see text] , fatigue, 3 h after exercise). In DIG, in resting muscle, [(3)H]‐ouabain binding site content (OB‐F(ab)) was unchanged; however, bound‐digoxin removal with Digibind revealed total ouabain binding (OB+F(ab)) 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‐F(ab) was increased at 67% [Formula: see text] (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. [Image: see text] 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 ([(3)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.