Peripheral fatigue: high-energy phosphates and hydrogen ions

PM R. 2010 May;2(5):347-58. doi: 10.1016/j.pmrj.2010.04.009.


Peripheral fatigue results from an overactivity-induced decline in muscle function that originates from non-central nervous system mechanisms. A common symptom of fatigue is a feeling of tiredness or weariness because of overexertion, such as that associated with intense or prolonged physical exercise. Fatigue is worsened by low physical fitness and chronic illnesses. These conditions may intensify fatigue to levels that limit physical and social functioning and severely diminish health-related quality of life. Although etiologic aspects of peripheral fatigue are often associated with regulatory system (neurologic, endocrine, immunologic, muscular) and support system (cardiovascular, pulmonary, metabolic, renal, digestive, skeletal) limitations, final mediation occurs in muscle cells as a result of altered crossbridge functioning. Specifically, the final product and ionic metabolite accumulation that result from adenosine triphosphate hydrolysis appear to inhibit crossbridge formation and activation. Thus, clinical manifestations of peripheral fatigue often can be observed as limitations placed upon muscle or cardiorespiratory endurance, here defined as fatigue resistance. An overview of the common pathways by which peripheral fatigue can be mediated is provided. Product inhibition of contractile chemistry is brought into focus as a common pathway through which the mechanisms of peripheral fatigue often act.

Publication types

  • Review

MeSH terms

  • Adenosine Triphosphate / analysis
  • Adenosine Triphosphate / metabolism
  • Energy Metabolism
  • Exercise / physiology
  • Fatigue / physiopathology*
  • Glycolysis / physiology
  • Humans
  • Hydrolysis
  • Mitochondria / metabolism
  • Motor Neurons / physiology
  • Muscle Contraction / physiology
  • Muscle Fibers, Skeletal / physiology
  • Muscle Strength / physiology
  • Phosphorylation
  • Physical Endurance / physiology


  • Adenosine Triphosphate