The bioenergetic capacity of skeletal muscle in a 17-year-old patient with a severe defect in complex III of the electron transport chain has been examined by 3tp NMR measurements of the molar ratio of phosphocreatine to inorganic phosphate (PCr/Pi). Resting ratios were 1.3-2.5, which can be compared with roughly 8.6 for a young, normal female control at rest. Quantitative evaluation of the activity of oxidative metabolism was afforded by the rate of recovery of PCr/P, from exercise and was found to be 2.5% of normal. After administration of menadione and ascorbate, we found a 21-fold increase of the recovery rate relative to the pretherapy value, to within 56% of the recovery rate of the young female control. Thus, NMR examinations of skeletal muscle at rest and in recovery from activity document marked improvement to specific drug therapy in the electron transport capabilities and the ATP synthesis rate of a patient with a deficiency in a cytochrome b-containing complex III. Improvements in functional ability, although not as dramatic as biochemical changes, are also apparent.NMR examination of excised skeletal muscle in vitro has enabled us to define limits to the thermodynamically related parameter of the molar ratio of phosphocreatine to inorganic phosphate (PCr/Pi) from its maximum >10 at rest (state 4) to a value of 1 for fully activated (state 3) oxidative metabolism, beyond which the activation of glycolytic energy metabolism causes severe tissue lactic acidosis. Similar observations of the human arm during measured exercise using a Cybex isokinetic ergometer and phosphorus NMR determination of PCr/Pj indicate that the ratio of energy expenditure to work output is approximately constant from the resting (state 4) to the maximally "aerobic" contracting muscle (state 3) (1). Human in vivo NMR spectroscopy has offered quantitation of energy performance in naive and trained skeletal muscle of the arm and the leg (2) as well as evidence of deficient oxygen supply to calf muscle in peripheral vascular disease (3,4). Similar studies have been performed on several inborn errors of metabolism, including McArdle disease (5), phosphofructokinase deficiency (3, 6), and an idiopathic cardiomyopathy (7). In moderate peripheral vascular disease and some metabolic diseases, oxygen delivery and tissue metabolism appear sufficient to allow adequate tissue level of ATP to maintain PCr/Pj > 2 with a correspondingly adequate thermodynamic capability.To quantitate the limits of PCr/Pj and improve the functional capability of patients with bioenergetic disabilities, we have studied the resting and limited-activity states of a patient with a deficiency of several polypeptides of complex III, including reducible cytochrome b, and greatly diminished ubiquinol-cytochrome c reductase activity. In attempting to improve the patient's thermodynamic capabilities by increasing the resting levels of PCr/Pj and accelerating recovery times, we have designed an appropriate bypass of the cytochrome b-deficient sites by redox mediato...

To evaluate possible progressive metabolic changes in Duchenne muscular dystrophy, we used 31P nuclear magnetic resonance spectroscopy to measure high-energy phosphate compounds and phosphorylated diesters (PDE) in resting gastrocnemius muscle of 14 Duchenne patients and 10 normal boys. The patients had higher inorganic phosphate (Pi), intracellular pH, and PDE; and lower phosphocreatine (PCr) and PCr/Pi ratio; ATP was not significantly different. The patients showed significant age-related decreases in PCr and PCr/Pi, and increases in Pi and PDE, but ATP did not change. In normal boys, ATP increased with age, but PCr and Pi did not. These studies imply progressive metabolic deterioration in Duchenne dystrophy.

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Embolization of cranial base tumors is an important part of the therapeutic armamentarium for the treatment of cranial base lesions. Recognition of the morbidity of this procedure will allow for the most appropriate use of this powerful adjunct to cranial base surgery.