The potassium-glycogen interaction on force and excitability in mouse skeletal muscle: implications for fatigue

A reduced muscle glycogen content and potassium (K⁺ ) disturbances across muscle membranes occur concomitantly during repeated intense exercise and together may contribute to skeletal muscle fatigue. Therefore, we examined whether raised extracellular K⁺ concentration ([K⁺ ]_o ) (4 to 11 mM) interacts with lowered glycogen to reduce force production. Isometric contractions were evoked in isolated mouse soleus muscles (37°C) using direct supramaximal field stimulation. (1) Glycogen declined markedly in non-fatigued muscle with >2 h exposure in glucose-free physiological saline compared with control solutions (11 mM glucose), i.e. to <45% control. (2) Severe glycogen depletion was associated with increased 5'-AMP-activated protein kinase activity, indicative of metabolic stress. (3) The decline of peak tetanic force at 11 mM [K⁺ ]_o was exacerbated from 67% initial at normal glycogen to 22% initial at lowered glycogen. This was due to a higher percentage of inexcitable fibres (71% vs. 43%), yet without greater sarcolemmal depolarisation or smaller amplitude action potentials. (4) Returning glucose while at 11 mM [K⁺ ]_o increased both glycogen and force. (5) Exposure to 4 mM [K⁺ ]_o glucose-free solutions (15 min) did not increase fatiguability during repeated tetani; however, after recovery there was a greater force decline at 11 mM [K⁺ ]_o at lower than normal glycogen. (6) An important exponential relationship was established between relative peak tetanic force at 11 mM [K⁺ ]_o and muscle glycogen content. These findings provide direct evidence of a synergistic interaction between raised [K⁺ ]_o and lowered muscle glycogen as the latter shifts the peak tetanic force-resting E_M relationship towards more negative resting E_M due to lowered sarcolemmal excitability, which hence may contribute to muscle fatigue. KEY POINTS: Diminished muscle glycogen levels and raised extracellular potassium concentrations ([K⁺ ]_o ) occur simultaneously during intense exercise and together may contribute to muscle fatigue. Prolonged exposure of isolated non-fatigued soleus muscles of mice to glucose-free physiological saline solutions markedly lowered muscle glycogen levels, as does fatigue then recovery in glucose-free solutions. For both approaches, the subsequent decline of maximal force at 11 mM [K⁺ ]_o , which mimics interstitial [K⁺ ] levels during intense exercise, was exacerbated at lowered compared with normal glycogen. This was mainly due to many more muscle fibres becoming inexcitable. We established an important relationship that provides evidence of a synergistic interaction between raised [K⁺ ]_o and lowered glycogen content to reduce force production. This paper indicates that partially lowered muscle glycogen (and/or metabolic stress) together with elevated interstitial [K⁺ ] interactively lowers muscle force, and hence may diminish performance especially during repeated high-intensity exercise.