The term metabolic myopathy refers to disorders that impair the metabolism of carbohydrates, lipids or both within skeletal muscle. Many of these disorders are associated with abnormal storage of glycogen (glycogen storage diseases) or triglyceride (lipid myopathies) but others, such as distal glycolytic defects and carnitine palmitoyltransferase II deficiency, usually do not result in excess muscle stores of glycogen or lipid. Some metabolic myopathies, notably acid maltase deficiency, affect nonenergy yielding pathways, but the majority of metabolic myopathies are inborn errors of muscle energy metabolism. The pathophysiology of these muscle energy defects relates directly to the role of the affected energy pathway in muscle function.

Muscle fuel at rest and during exercise

The fundamental source of energy for muscle contraction and ion transport is the hydrolysis of adenosine triphosphate (ATP) to ADP and inorganic phosphate (Pi). ADP and Pi in turn activate energy-producing reactions that regenerate ATP via anaerobic or oxidative means. The major anaerobic sources of ADP phosphorylation are the hydrolysis of phosphocreatine (PCr) via the creatine kinase reaction, and anaerobic glycogenolysis in which glycogen is metabolized to lactic acid. Anaerobic energy pathways are the major or sole source of ATP production when muscle blood flow is compromised as in ischemic or isometric exercise, e.g. weight lifting, or when energy demand exceeds the limits of oxidative power output, e.g. maximal effort running. Anaerobic sources of energy have several advantageous features: (i) they are intrinsic to muscle and independent of blood flow or oxygen supply; (ii) they enable muscle to work for brief periods at rates of ATP production (power output) that are two- to threefold higher than those available through oxidative metabolism; and (iii) they can reach these high rates of energy turnover in seconds, whereas acceleration to maximal oxidative power output takes 3–30 minutes (Sahlin, 1986). On the negative side, anaerobic sources of energy are rapidly depleted and/or lead to the accumulation of metabolic end products, e.g. protons, inorganic phosphate, and ADP, that are associated with muscle fatigue (see below) (Fitts, 1994). No human defects in PCr metabolism attributable to inborn errors of creatine kinase have been recognized, although genetic ‘knockout’ animal models of both cytoplasmic and mitochondrial forms of creatine kinase have been produced.