Metabolic Factors Contributing to Altered Ca2+ Regulation in Skeletal Muscle Fatigue

Acta Physiol Scand. 2003 Sep;179(1):39-48. doi: 10.1046/j.1365-201X.2003.01169.x.


Aim: Skeletal muscle fatigue is characterized by a failure to maintain force production or power output during intense exercise. Many recent studies on isolated fibres have used brief repetitive tetanic contractions to mimic fatigue resulting from intensive exercise and to investigate the underlying cellular mechanisms. Such studies have shown that characteristic changes in Ca2+ regulation occur during fatiguing stimulation. This includes prolongation of the 'Ca2+-tails' which follow each period of tetanic stimulation and a progressive rise in resting [Ca2+]. More importantly, the final stage of fatigue is associated with a rapid decrease in tetanic [Ca2+]i and force. These fatigue-induced changes in sarcoplasmic reticulum (SR) Ca2+ regulation are temporally associated with alterations in the intracellular levels of phosphate metabolites and a causal relationship has often been proposed. The aim of this review is to evaluate the evidence linking changes in the levels of phosphate metabolites and altered Ca2+ regulation during fatigue.

Results: The following current hypotheses will be discussed: (1) the early changes in Ca2+ regulation reflect alterations in the intracellular levels of phosphate metabolites, (2) inhibition of the SR Ca2+ release mechanism (e.g. caused by ATP depletion and increased [Mg2+]) contributes to the decrease in tetanic [Ca2+]i during the final stages of fatigue and (iii) delayed entry of inorganic phosphate ions (Pi) into the SR, followed by precipitation of calcium phosphate (Ca-Pi), can explain the fatigue-induced decrease in tetanic [Ca2+]i.

Conclusion: There is strong evidence that changes in phosphate metabolite levels contribute to early changes in SR Ca2+ regulation during fatigue and that inhibition of the SR Ca2+ release mechanism can partially explain the rapid decrease in tetanic [Ca2+]i during the final stages of fatigue. While precipitation of Ca-Pi may occur within the SR during fatigue, there is currently insufficient evidence to establish whether this contributes to the late decline in tetanic [Ca2+]i.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Humans
  • Muscle Fatigue / physiology*
  • Muscle, Skeletal / metabolism*
  • Phosphates / metabolism
  • Sarcoplasmic Reticulum / metabolism


  • Phosphates
  • Calcium