Na⁺-K⁺Pump Regulation and Skeletal Muscle Contractility

Abstract

In skeletal muscle, excitation may cause loss of K+, increased extracellular K+ ([K+]o), intracellular Na+ ([Na+]i), and depolarization. Since these events interfere with excitability, the processes of excitation can be self-limiting. During work, therefore, the impending loss of excitability has to be counterbalanced by prompt restoration of Na+-K+ gradients. Since this is the major function of the Na+-K+ pumps, it is crucial that their activity and capacity are adequate. This is achieved in two ways: 1) by acute activation of the Na+-K+ pumps and 2) by long-term regulation of Na+-K+ pump content or capacity. 1) Depending on frequency of stimulation, excitation may activate up to all of the Na+-K+ pumps available within 10 s, causing up to 22-fold increase in Na+ efflux. Activation of the Na+-K+ pumps by hormones is slower and less pronounced. When muscles are inhibited by high [K+]o or low [Na+]o, acute hormone- or excitation-induced activation of the Na+-K+ pumps can restore excitability and contractile force in 10-20 min. Conversely, inhibition of the Na+-K+ pumps by ouabain leads to progressive loss of contractility and endurance. 2) Na+-K+ pump content is upregulated by training, thyroid hormones, insulin, glucocorticoids, and K+ overload. Downregulation is seen during immobilization, K+ deficiency, hypoxia, heart failure, hypothyroidism, starvation, diabetes, alcoholism, myotonic dystrophy, and McArdle disease. Reduced Na+-K+ pump content leads to loss of contractility and endurance, possibly contributing to the fatigue associated with several of these conditions. Increasing excitation-induced Na+ influx by augmenting the open-time or the content of Na+ channels reduces contractile endurance. Excitability and contractility depend on the ratio between passive Na+-K+ leaks and Na+-K+ pump activity, the passive leaks often playing a dominant role. The Na+-K+ pump is a central target for regulation of Na+-K+ distribution and excitability, essential for second-to-second ongoing maintenance of excitability during work.

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

“…The effects of Ca 2+ observed in this study are also consistent with the observation that in normal muscle fibers, increased [Ca 2+ ] o hyperpolarizes the resting membrane potential (36) (16,45). Increased [Na + ] i is an important factor for activation of the Na + /K + pump (50,51), and Na + /K + pump stimulation improves membrane excitability and contractility in normal muscles with reduced Na + and/or K + gradients (52)(53)(54). We observed that partial inhibition of the pump with 0.5 μM ouabain exacerbated the K + effect on EDL muscle and drastically reduced the transient recovery observed at high [K + ] o .…”

Salbutamol effects on systemic potassium dynamics during and following intense continuous and intermittent exercise

“…Salbutamol stimulates NKA in isolated skeletal muscle from rats (Clausen 2003), an effect that was not synergistic with muscle stimulation (Clausen and Flatman 1980). Terbutaline was recently shown to protect against an exercise-induced decline in NKA activity (Hostrup et al 2014b) and other β-adrenergic agonists also induced K + -lowering effects during continuous exercise in humans (Hallen et al 1996;Rolett et al 1990); this effect was reversed with β-blockers, resulting in greater elevations in K + Katz et al 1985).…”

“…Potassium clearance during exercise also occurs via uptake by other non-contracting or relatively inactive muscles, and also splanchnic K + uptake (Lindinger 1995;Sejersted and Sjøgaard 2000;Clausen 2003 (Hostrup et al 2014a;Collomp et al 2000;Grove et al 1995;Newnham et al 1993;Van Baak et al 2000), or in samples drawn only after completion of, rather than during exercise (Hostrup et al 2014a;Kalsen et al 2014;Hostrup et al 2014b;Larsson et al 1997;Grove et al 1995); and/or utilised oral salbutamol (Collomp et al 2000;Van Baak et al 2000;Hostrup et al 2014a;Goubault et al 2001 after prolonged cycling to exhaustion (Van Baak et al 2000), or at 5-10 min recovery after repeated 30 s sprints or repeated bouts of high intensity cycling, although greater reductions were evident at 1 or 2 min after some individual bouts (Hostrup et al 2014a). Similarly, after salbutamol inhalation (800 µg), there was no further change in antecubital venous [K + ] at 2-10 min after exhaustive cycling at 85% VO 2peak (Goubault et al 2001).…”

“…Marked K + shifts occur from intracellular to extracellular fluid in contracting muscles and then into plasma; rapid and precise control of these K + shifts is essential for maintaining muscle excitability and is regulated by the Na + ,K + -ATPase (Na + ,K + -pump, NKA) and other K + transport proteins in skeletal muscle (Clausen 2013b;McKenna et al 2008;Sejersted and Sjøgaard 2000;McDonough and Youn 2005;Clausen 2013a). Pronounced increases in circulating catecholamines occur during intense exercise (Kjaer 1989), which activate NKA in skeletal muscle (Clausen 2003 (Hallen et al 1996).…”

Estudo da condução nervosa motora na doença de McArdle: relato de caso

“…Haller et al 9 encontraram concentrações reduzidas da bomba de sódio-potássio (Na + K + -AT Pase) na membrana da fibra muscular de pacientes com DM, provocando aumento da concentração extracelular do potássio. Isso reduz a excitabilidade da membrana durante o período de contração m u s c u l a r, explicando a diminuição do PAMC após esforço e ao estímulo repetitivo 9,10 . O mecanismo responsável pela redução da Na + K + -ATPase nos pacientes com DM não está totalmente elucidado, mas pode estar relacionado com um inadequado suprimento de ATP proveniente da glicólise para a bomba de Na + K + da fibra muscular 10 .…”