N‐acetylcysteine attenuates the decline in muscle Na⁺,K⁺‐pump activity and delays fatigue during prolonged exercise in humans

Abstract

Reactive oxygen species (ROS) have been linked with both depressed Na + ,K + -pump activity and skeletal muscle fatigue. This study investigated N -acetylcysteine (NAC) effects on muscle Na + ,K + -pump activity and potassium (K + ) regulation during prolonged, submaximal endurance exercise. Eight well-trained subjects participated in a double-blind, randomised, crossover design, receiving either NAC or saline (CON) intravenous infusion at 125 mg kgfor 15 min, then 25 mg kg −1 h −1 for 20 min prior to and throughout exercise. Subjects cycled for 45 min at 71%V O 2 peak , then continued at 92%V O 2 peak until fatigue. Vastus lateralis muscle biopsies were taken before exercise, at 45 min and fatigue and analysed for maximal in vitro Na + ,K + -pump activity (K + -stimulated 3-O-methyfluorescein phosphatase; 3-O-MFPase). Arterialized venous blood was sampled throughout exercise and analysed for plasma K + and other electrolytes. Time to fatigue at 92%V O 2 peak was reproducible in preliminary trials (C.V. 5.6 ± 0.6%) and was prolonged with NAC by 23.8 ± 8.3% (NAC 6.3 ± 0.5 versus CON 5.2 ± 0.6 min, P < 0.05). Maximal 3-O-MFPase activity decreased from rest by 21.6 ± 2.8% at 45 min and by 23.9 ± 2.3% at fatigue (P < 0.05). NAC attenuated the percentage decline in maximal 3-O-MFPase activity (%Δactivity) at 45 min (P < 0.05) but not at fatigue. When expressed relative to work done, the %Δactivity-to-work ratio was attenuated by NAC at 45 min and fatigue (P < 0.005). The rise in plasma [K + ] during exercise and the Δ[K + ]-to-work ratio at fatigue were attenuated by NAC (P < 0.05). These results confirm that the antioxidant NAC attenuates muscle fatigue, in part via improved K + regulation, and point to a role for ROS in muscle fatigue.

Regulação metabólica e produção de espécies reativas de oxigênio durante a contração muscular: efeito do glicogênio na manutenção do estado redox intracelular

“…No tecido muscular esquelético, a oxidação de glutationa excede a capacidade intracelular de reoxidação, resultando em aumento na razão glutationa oxidada/glutationa reduzida (1,3,4) . Nessas condições, o fígado aumenta a liberação de glutationa para o sangue, elevando a captação e a capacidade antioxidante do tecido muscular durante o processo de contração.…”

“…Dessa forma, estamos propondo neste estudo, um mecanismo metabólico adicional, pelo qual o aumento da produção de espécies reativas de oxigênio aceleraria os processos de fadiga durante contrações musculares intensas. Quando a oxidação de glutationa é baixa, grande parte da glutationa oxidada produzida no tecido muscular pode ser rapidamente regenerada pelo sistema glutationa redutase/NADPH + (3,4,24) . Porém, alterações do balanço redox para um estado mais oxidado pode comprometer a capacidade desse sistema, favorecendo a ocorrência de estresse oxidativo (2,3,7,26) .…”

“…Há muitas evidências de que a glutationa é um dos principais antioxidantes do tecido muscular esquelético exercendo função vital na manutenção do estado redox intracelular durante a contração (1)(2)(3) e protegendo este tecido contra o ataque oxidativo imposto pela elevada taxa metabólica durante o exercício (3,4) . Em adição, várias proteínas incluindo proteínas quinases, fatores de transcrição e enzimas do metabolismo celular possuem propriedades redox sensitivas em resíduos de cisteína ricos em grupos tióis (2) .…”

N-acetylcysteine Protects Striated Muscle in a Model of Compartment Syndrome

“…NAC also reduces oxidative burst activity but enhances phagocytosis in rodent and human neutrophils [13,17]. NAC is particularly suitable for the attenuation of oxidant-mediated injury as it not only has a direct antioxidant effect by means of free-radical scavenging properties but also replenishes depleted cellular glutathione stores restoring intrinsic cellular antioxidant defenses [6,13,32,50]. The widely accepted use of NAC in current clinical practice confers an additional advantage for its potential use in the context of CS, IRI, or trauma, as the toxicity profile of the drug is well established and clinicians already are experienced in its use.…”

Role of phospholemman and the 70 kDa inhibitor protein in regulating Na+/K+ ATPase activity in pulmonary artery smooth muscle cells under U46619 stimulation

“…It may provide an alternative to phosphorylation of the NKA or associated FXYD because the pump's subunits contain residues that can be oxidized (e.g. the sulfhydryl group) [12] and it has been shown that NKA in skeletal muscle is redox sensitive [13]. Bibert et al [12] recently showed that angiotensin II induces PKC activity and that leads to ROS generation, which subsequently causes glutathionylation of the b subunit and hence inhibits NKA activity.…”