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 degrees 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.

Automated summary

During repeated intense exercise, a decrease in muscle glycogen content and disturbances in potassium (K+) concentration across muscle membranes occur simultaneously, contributing to skeletal muscle fatigue. This study aimed to investigate the interaction between elevated extracellular K+ concentration and reduced glycogen on force production. The results showed that severe depletion of glycogen led to a significant decline in force production, and the decline was exacerbated at elevated extracellular K+ concentration. Additionally, the replenishment of glucose increased both glycogen content and force production. These findings provide direct evidence of the synergistic interaction between elevated extracellular K+ concentration and reduced muscle glycogen, which may contribute to muscle fatigue by shifting the resting-force relationship towards a more negative resting membrane potential.