Yet another distinguishing feature described by Haller and Vissing is the opposite effect of glucose administration in the two diseases. Patients with McArdle disease benefit from glucose administration or from a sucrose load before exercise (9) because their metabolic block, which is far upstream in carbohydrate metabolism, impairs glycogen but not glucose utilization (Fig. ​(Fig.3).3). In contrast, meals rich in carbohydrate exacerbate the exercise intolerance of patients with phosphofructokinase (PFK)

deficiency for two reasons: (i) due to the metabolic block downstream in glycolysis, their muscle cannot utilize either glycogen or glucose; (ii) Inhibitors,research,lifescience,medical glucose decreases the blood concentration of the alternative fuels FFA and ketones, Inhibitors,research,lifescience,medical a situation dubbed the “out of wind” phenomenon (10). In 1980, while studying two patients with PFK deficiency, we noted, much to our surprise, that their muscle biopsies showed, in addition to deposits of normal-looking glycogen,

pockets of an abnormal polysaccharide with the histochemical and ultrastructural features of polyglucosan (11): the polysaccharide was intensely PAS-positive Inhibitors,research,lifescience,medical but only partially digested by diastase and, in the electron microscope, consisted of finely granular and 3-MA order fibrillar material, similar to the amylopectin-like storage material of GSD IV (branching enzyme deficiency). Based on experiments in E. coli (12), we reasoned that the high concentration of glucose 6 phosphate (G6P) resulting from the metabolic block would activate glycogen synthetase abnormally and alter the normal Inhibitors,research,lifescience,medical ratio of glycogen synthetase (GS) to branching enzyme (BE) to the advantage of GS, thus favoring the synthesis of polysaccharide with excessively long and poorly ramified chains (polyglucosan). In a serendipitous but spectacular

experiment, Raben et al. verified this mechanism when they overexpressed GS in the muscle of transgenic mice lacking acid maltase and observed massive accumulation of polyglucosan (13). The Inhibitors,research,lifescience,medical crucial role of the GS/BE ratio in the synthesis of normal glycogen has been confirmed in other conditions, such as cardiac glycogenoses due to defects in AMP-dependent protein kinase (AMPK) (14) and, possibly, in Lafora disease (this issue). The pathogenesis of rhabdomyolysis and myoglobinuria in McArdle CYTH4 disease, as in other glycogenoses, remains unclear. There is no doubt that the block of aerobic glycolysis or, sometimes, anaerobic glycolysis during intense exercise results in an “energy crisis”. However, neither old biochemical determinations in muscle biopsies taken during an exercise-induced contracture (15) nor more recent 31P magnetic resonance spectroscopic studies during controlled exercise (1, 16) have ever revealed a critical decrease of ATP.