A century of exercise physiology: effects of muscle contraction and exercise on skeletal muscle Na⁺,K⁺-ATPase, Na⁺ and K⁺ ions, and on plasma K⁺ concentration—historical developments

This historical review traces key discoveries regarding K⁺ and Na⁺ ions in skeletal muscle at rest and with exercise, including contents and concentrations, Na⁺,K⁺-ATPase (NKA) and exercise effects on plasma [K⁺] in humans. Following initial measures in 1896 of muscle contents in various species, including humans, electrical stimulation of animal muscle showed K⁺ loss and gains in Na⁺, Cl⁻ and H₂0, then subsequently bidirectional muscle K⁺ and Na⁺ fluxes. After NKA discovery in 1957, methods were developed to quantify muscle NKA activity via rates of ATP hydrolysis, Na⁺/K⁺ radioisotope fluxes, [³H]-ouabain binding and phosphatase activity. Since then, it became clear that NKA plays a central role in Na⁺/K⁺ homeostasis and that NKA content and activity are regulated by muscle contractions and numerous hormones. During intense exercise in humans, muscle intracellular [K⁺] falls by 21 mM (range − 13 to − 39 mM), interstitial [K⁺] increases to 12–13 mM, and plasma [K⁺] rises to 6–8 mM, whilst post-exercise plasma [K⁺] falls rapidly, reflecting increased muscle NKA activity. Contractions were shown to increase NKA activity in proportion to activation frequency in animal intact muscle preparations. In human muscle, [³H]-ouabain-binding content fully quantifies NKA content, whilst the method mainly detects α₂ isoforms in rats. Acute or chronic exercise affects human muscle K⁺, NKA content, activity, isoforms and phospholemman (FXYD1). Numerous hormones, pharmacological and dietary interventions, altered acid–base or redox states, exercise training and physical inactivity modulate plasma [K⁺] during exercise. Finally, historical research approaches largely excluded female participants and typically used very small sample sizes.