An 8-year-old boy is evaluated for exercise intolerance. The patient experiences fatigue, muscle pain, and cramps during exercise as well as severe muscle stiffness following strenuous activity. Physical examination is unremarkable. A forearm ischemic exercise test is performed by applying a blood pressure cuff on the patient's exercising forearm and sampling blood lactate several minutes after the exercise. The patient's blood samples show no rise in lactate levels. Biochemical analysis of a muscle biopsy reveals absent lactate dehydrogenase activity. In this patient, strenuous exercise leads to inhibition of glycolysis in skeletal muscle due to intracellular depletion of which of the following substances?

Question

An 8-year-old boy is evaluated for exercise intolerance.  The patient experiences fatigue, muscle pain, and cramps during exercise as well as severe muscle stiffness following strenuous activity.  Physical examination is unremarkable.  A forearm ischemic exercise test is performed by applying a blood pressure cuff on the patient's exercising forearm and sampling blood lactate several minutes after the exercise.  The patient's blood samples show no rise in lactate levels.  Biochemical analysis of a muscle biopsy reveals absent lactate dehydrogenase activity.  In this patient, strenuous exercise leads to inhibition of glycolysis in skeletal muscle due to intracellular depletion of which of the following substances?

Quizplus · Accepted Answer

11ec160b_36a3_ac0c_9249_f562f09f4960_MD0001_00 In glycolysis, glucose is metabolized to pyruvate. Under aerobic conditions, pyruvate is converted to acetyl-CoA to enter the tricarboxylic acid (TCA) cycle. When oxygen is depleted (eg, in exercising muscle), pyruvate is converted to lactate (anaerobic glycolysis). During glycolysis, glyceraldehyde-3-phosphate (G3P) is converted to 1-3-bisphosphoglycerate (BPG) by the enzyme G3P dehydrogenase. This enzyme reduces NAD⁺ to NADH. NAD⁺ is present in limited amounts in most cells, and it must be regenerated from NADH for glycolysis to continue. Under aerobic conditions, NAD⁺ is converted to NADH in the TCA cycle. NADH is then reconverted to NAD⁺ in the electron transport chain as the energy in NADH is utilized to synthesize ATP. In anaerobic glycolysis, NAD+ is regenerated from NADH when pyruvate is converted to lactate via lactate dehydrogenase. In patients with lactate dehydrogenase deficiency, glycolysis is inhibited in strenuously exercising muscle as muscle cells cannot regenerate NAD⁺. Consequently, high-intensity physical activity leads to muscle breakdown, pain, and fatigue as insufficient amounts of energy are being produced in the exercising muscle. (Choice A) During muscle contraction, glycogen is broken down via glycogen phosphorylase for energy production by the glycolytic pathway. Epinephrine causes cyclic AMP-mediated phosphorylation of glycogen phosphorylase, which activates this enzyme. Non-phosphorylation-dependent activation of glycogen phosphorylase can occur during muscle contraction via increased intracellular calcium concentrations and via AMP under extreme conditions. (Choice B) Carnitine is an amino acid derivative responsible for transporting fatty acids into the mitochondria for beta-oxidation. Carnitine is synthesized from lysine and methionine; vitamin C is essential for this synthesis. (Choice C) Citrate is formed from the condensation of acetyl CoA with oxaloacetate in the first step of the TCA cycle. Increased citrate concentrations decrease glycolysis as citrate is a powerful allosteric inhibitor of phosphofructokinase-1. In exercising muscles under anaerobic conditions, oxidative phosphorylation of glucose through the citric acid cycle is not a dominant pathway; therefore, excess citrate is not produced. (Choice D) FADH₂ is not produced in glycolysis. FADH₂ is produced from FAD during the conversion of succinate to fumarate in the TCA cycle by the enzyme succinate dehydrogenase. (Choice F) In glycolysis, pyruvate is formed from phosphoenolpyruvate by a unidirectional enzyme called pyruvate kinase. In the absence of lactate dehydrogenase activity, pyruvate will accumulate in the cell under anaerobic conditions. Educational objective: Under anaerobic conditions, NADH transfers electrons to pyruvate to form lactate and regenerate NAD⁺. NAD⁺ is required to convert glyceraldehyde-3-phosphate to 1-3-bisphosphoglycerate in glycolysis. __________ References: Lactate dehydrogenase M-subunit deficiencies: clinical features, metabolic background, and genetic heterogeneities. (http://www.ncbi.nlm.nih.gov/pubmed/7603529)

An 8-Year-Old Boy Is Evaluated for Exercise Intolerance