Sostaric, Simon ORCID: 0000-0003-0701-0992, Petersen, Aaron ORCID: 0000-0003-1508-748X, Goodman, Craig ORCID: 0000-0002-5874-7743, Gong, Xiaofei, Aw, Tai-Juan ORCID: 0000-0001-8363-9499, Brown, Malcolm J ORCID: 0000-0003-1667-7801, Garnham, Andrew ORCID: 0000-0001-8068-9300, Steward, Collene ORCID: 0000-0002-7903-0346, Murphy, Kate T ORCID: 0000-0003-1993-4367, Carey, Kate A ORCID: 0000-0002-5748-0768, Leppik, James ORCID: 0000-0002-3040-081X, Fraser, Steve F ORCID: 0000-0003-0202-9619, Cameron-Smith, David ORCID: 0000-0002-0144-5816, Krum, Henry ORCID: 0000-0002-0655-3015, Snow, Rodney J ORCID: 0000-0002-4796-6916 and McKenna, Michael ORCID: 0000-0001-9998-0093 (2022) Oral digoxin effects on exercise performance, K+ regulation and skeletal muscle Na+, K+-ATPase in healthy humans. Journal of Physiology, 600 (16). pp. 3749-3774. ISSN 0022-3751

Abstract

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 presented.) and 67% (Formula presented.), 90% (Formula presented.) 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 presented.), fatigue, 3 h after exercise). In DIG, in resting muscle, [3H]-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% (Formula presented.) (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. (Figure presented.). 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 ([3H]-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.

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