The pathophysiology of McArdle's disease: Clues to regulation in exercise and fatigue

S. F. Lewis, R. G. Haller

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Abstract

Muscle phosphorylase deficiency (McArdle's disease) has conventionally been considered a disorder of glycogenolysis, and the associated impairment in oxidative metabolism has been largely overlooked. Muscle glycogen normally is the primary oxidative fuel at exercise work loads requiring more than 75-80% of maximal O2 uptake (V̇(O2(max))). Evidence is presented to support the hypothesis that a limited flux through the Embden-Myerhof pathway in McArdle's disease reduces the capacity to generate NADH required to support a normal V̇(O2(max)). The extent of the oxidative defect is substrate dependent; i.e., it can be partially corrected by increasing the availability of alternative oxidative substrates (e.g., glucose, free fatty acids) to working muscle. Experiments employing modification of substrate availability closely link 1) the hyperkinetic circulatory response to exercise (i.e., an abnormally large increase in O2 transport to skeletal muscle) and 2) the premature muscle fatigue and cramping of McArdle patients with their oxidative impairment and suggest that a metabolic common denominator in these abnormal responses may be a pronounced decline in the muscle phosphorylation potential ([ATP]/[ADP][P(i)]). The hyperkinetic circulation likely is mediated by the local effects on metabolically sensitive skeletal muscle afferents and vascular smooth muscle of K+, P(i), or adenosine or a combination of these substances released excessively from working skeletal muscle. The premature muscle fatigue and cramping of McArdle patients does not appear to be due to depletion of ATP but is associated with an increased accumulation of P(i) and probably ADP in skeletal muscle. Accumulations of P(i) and ADP are known to inhibit the myofibrillar, Ca2+, and Na+-K+-ATPase reactions.

Original languageEnglish (US)
Pages (from-to)391-401
Number of pages11
JournalJournal of applied physiology
Volume61
Issue number2
DOIs
StatePublished - Jan 1 1986

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ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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