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, linger flexion (FF, 105%(peak-workrate), 3 x 1 min, fourth bout to fatigue) and leg cycling (LC, 10 min at 33% V-O2(pea)k and 67% V-O2peak, 90% V-O2peak 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% V-O2peak, fatigue, 3 h after exercise). In DIG, in resting muscle, [H-3]-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% V-O2peak (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 F, F 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.