Acute oral digoxin in healthy adults hastens fatigue and increases plasma K+ during intense exercise, despite preserved skeletal muscle Na+,K+-ATPase

We investigated acute effects of the Na⁺,K⁺-ATPase (NKA) inhibitor, digoxin, on muscle NKA content and isoforms, arterial plasma [K⁺] ([K⁺]_a) and fatigue with intense exercise. In a randomised, crossover, double-blind design, 10 healthy adults ingested 0.50 mg digoxin (DIG) or placebo (CON) 60 min before cycling for 1 min at 60% ${\dot{V}}_{O_2\mathrm{peak}}$ then at 95% ${\dot{V}}_{O_2\mathrm{peak}}$ until fatigue. Pre- and post-exercise muscle biopsies were analysed for [³H]-ouabain binding site content without (OB-F_ab) and after incubation in digoxin antibody (OB+F_ab) and NKA α_1-2 and β_1-2 isoform proteins. In DIG, pre-exercise serum [digoxin] reached 3.36 (0.80) nM [mean (SD)] and muscle NKA–digoxin occupancy was 8.2%. Muscle OB-F_ab did not differ between trials, whereas OB+F_ab was higher in DIG than CON (8.1%, treatment main effect, P = 0.001), whilst muscle NKA α_1-2 and β_1-2 abundances were unchanged by digoxin. Fatigue occurred earlier in DIG than CON [−7.7%, 2.90 (0.77) vs. 3.14 (0.86) min, respectively; P = 0.037]. [K⁺]_a increased during exercise until 1 min post-exercise (P = 0.001), and fell below baseline at 3–10 (P = 0.001) and 20 min post-exercise (P = 0.022, time main effect). In DIG, [K⁺]_a (P = 0.035, treatment effect) and [K⁺]_a rise pre-fatigue were greater [1.64 (0.73) vs. 1.55 (0.73), P = 0.016], with lesser post-exercise [K⁺]_a decline than CON [−2.55 (0.71) vs. −2.74 (0.62) mM, respectively, P = 0.003]. Preserved muscle OB-F_ab with digoxin, yet increased OB+F_ab with unchanged NKA isoforms, suggests a rapid regulatory assembly of existing NKA α and β subunits exists to preserve muscle NKA capacity. Nonetheless, functional protection against digoxin was incomplete, with earlier fatigue and perturbed [K⁺]_a with exercise.

Key points

• Intense exercise causes marked potassium (K⁺) shifts out of contracting muscle cells, which may contribute to muscle fatigue.
• Muscle and systemic K⁺ perturbations with exercise are largely regulated by increased activity of Na⁺,K⁺-ATPase in muscle, which can be specifically inhibited by the cardiac glycoside, digoxin.
• We found that acute oral digoxin in healthy adults reduced time to fatigue during intense exercise, elevated the rise in arterial plasma K⁺ concentration during exercise and slowed K⁺ concentration decline post-exercise.
• Muscle functional Na⁺,K⁺-ATPase content was not reduced by acute digoxin, despite an 8.2% digoxin occupancy, and was unchanged at fatigue. Muscle Na⁺,K⁺-ATPase isoform protein abundances were unchanged by digoxin or fatigue. These suggest possible rapid assembly of existing subunits into functional pumps.
• Thus, acute digoxin impaired performance and exacerbated plasma K⁺ disturbances with intense, fatiguing exercise in healthy participants. These occurred despite the preservation of functional Na⁺,K⁺-ATPase in muscle.