J Physiol. 2022 Jul 15.
Simon Sostaric,
Aaron C Petersen,
Craig A Goodman,
Xiaofei Gong,
Tai-Juan Aw,
Malcolm J Brown,
Andrew Garnham,
Collene H Steward,
Kate T Murphy,
Kate A Carey,
James Leppik,
Steve F Fraser,
David Cameron-Smith,
Henry Krum,
Rodney J Snow,
Michael J McKenna.
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 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.ABSTRACT: We investigated whether digoxin lowered muscle Na+ ,K+ -ATPase (NKA), impaired muscle performance and exacerbated exercise K+ disturbances. Ten healthy adults ingested digoxin (0.25mg; DIG) or placebo (CON) for 14 d 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%VO2peak and 67%VO2peak , 90%VO2peak 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%VO2peak , fatigue, 3h post-exercise). In DIG, in resting muscle, [3 H]-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%VO2peak (wet-weight-1 , P = 0.005; protein-1 P = 0.001) and at fatigue (protein-1 , 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. Abstract figure legend Digoxin specifically inhibits Na ,K -pumps in all tissues and in skeletal muscle, could therefore impair cellular Na /K homeostasis, excitability and contractility. In heart failure patients, digoxin binds to and therefore reduces the Na ,K -pump content in skeletal muscle; this lower number of available functional Na ,K -pumps is consistent with an elevated circulating [K ] during exercise. We show here in healthy volunteers, that oral digoxin intake which resulted in therapeutic [digoxin], did not reduce the muscle Na ,K -pump content, which was unchanged. However, measures with digibind revealed the total number of Na ,K -pumps was elevated by 8percent. Digoxin did not affect either arterial [K ] or time to fatigue, during both finger flexion exercise and leg cycling exercise. This indicates a remarkable preservation of skeletal muscle Na ,K -pumps and thus also of circulating [K ] and performance during fatiguing, intense exercise challenges. However, one adverse consequence of digoxin was a 4percent reduction in muscle strength. This article is protected by copyright. All rights reserved.
Keywords: digoxin; exercise; muscle strength; ouabain; potassium; skeletal muscle fatigue; sodium-potassium pump