​(Fig.1).1). During submaximal exercise of moderate

intensity (< 50% vO2max), muscle initially utilizes blood glucose, but – as the exercise continues beyond a few hours – there is a gradual shift from the oxidation of glucose, a finite fuel derived from liver glycogen, to the oxidation of fatty acids, a virtually inexhaustible fuel derived from fat stores (1). Figure 1 elected metabolic pathways in a schematic rendition of a mitochondrion. The spirals indicate the sequential reactions of the β-oxidation pathway, resulting in the liberation of acetyl-coenzyme A (CoA) and the Inhibitors,research,lifescience,medical reduction of flavoprotein. Abbreviations: ... Two reactions are immediate sources of energy: (i) the creatine kinase (CK) reaction that breaks phosphocreatine Inhibitors,research,lifescience,medical (PCr) down to ATP and creatine in the presence of ADP through the creatine kinase (CK) reaction (PCr + ADP + H+ = ATP + Cr); and (ii) the adenylate kinase reaction, generating ATP and AMP from the condensation of two molecules of ADP (2ADP = ATP + AMP). However, by far the largest amount of energy for exercise derives from Inhibitors,research,lifescience,medical oxidative phosphorylation in the mitochondria and a much smaller amount of energy comes from anaerobic glycolysis, which is crucial only during isometric contraction (when blood supply is virtually cut off). The still widely

held belief that the exercise Inhibitors,research,lifescience,medical intolerance that characterizes many glycogenoses is due to a block of anaerobic glycolysis is exaggerated and probably due to the popularity of the forearm ischemic exercise introduced by Brian McArdle in 1951 (2). In truth, the pathophysiology of exercise intolerance in McArdle Inhibitors,research,lifescience,medical disease and similar muscle glycogenoses is mostly due

to a block of aerobic glycolysis. Disorders of energy supply to muscle, irrespective of whether the defects involve carbohydrate metabolism, lipid metabolism, or the respiratory chain, result in one of two syndromes: (i) exercise intolerance, often punctuated by recurrent and reversible “crises” of muscle breakdown (rhabdomyolysis) Brefeldin_A and myoglobinuria; or (ii) chronic subacute weakness (Fig. ​(Fig.2).2). Focusing our attention on the glycogenoses, all defects associated with the former syndrome involve glycogen breakdown or glycolysis and are triggered by exercise, whereas the latter syndrome is associated with defects in a glycogen synthetic enzyme (brancher), the lysosomal glycogenolytic enzyme (acid maltase [α-glucosidase]), one glycolytic enzyme (aldolase), and, rather surprisingly, a glycogenolytic enzyme (debrancher) that works hand-in-hand with myophosphorylase The pathogenesis of weakness in the second group of glycogenoses is not completely clear. In part, at least, it Ruxolitinib 941678-49-5 relates to the multisystem nature of the enzyme defects.