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Oral digoxin effects on exercise performance, K + regulation and skeletal muscle Na + ,K + ‐ATPase in healthy humans
Author(s) -
Sostaric Simon,
Petersen Aaron C.,
Goodman Craig A.,
Gong Xiaofei,
Aw TaiJuan,
Brown Malcolm J.,
Garnham Andrew,
Steward Collene H.,
Murphy Kate T.,
Carey Kate A.,
Leppik James,
Fraser Steve F.,
CameronSmith David,
Krum Henry,
Snow Rodney J.,
McKenna Michael J.
Publication year - 2022
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp283017
Subject(s) - digoxin , ouabain , medicine , chemistry , skeletal muscle , heart failure , endocrinology , sodium , organic chemistry
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%V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ and 67%V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ , 90%V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ 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 O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ , 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%V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ (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.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.