Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect. R G Haller, … , K Ayyad, C G Blomqvist J Clin Invest. 1991;88(4):1197-1206. https://doi.org/10.1172/JCI115422. Research Article We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39 +/- 5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a- v O2 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7 +/- 2.1) despite normal oxygen carrying capacity and Hgb-O2 P50. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Qmax, patient = 303 ml/min per kg, normal men 238 +/- 36) and the slope of increase in Q relative to VO2 (i.e., delta Q/delta VO2) from rest to exercise was exaggerated (delta Q/delta VO2, patient = 29, normal men = 4.7 +/- 0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at […] Find the latest version: https://jci.me/115422/pdf Deficiency of Skeletal Muscle Succinate Dehydrogenase and Aconitase Pathophysiology of Exercise in a Novel Human Muscle Oxidative Defect Ronald G. HaIler, K. G. Henrikason, Lennart Jorfeldt, Eric Hultman, Rolf Wibom, Kent Sahlin, Nils-Holger Areskog, Marguerite Gunder, Karen Ayyad, C. Gunnar Blomqvist, Robin E. Hall, Phillippe Thuillier, Nancy G. Kennaway, and Steven F. Lewis Departments ofNeurology, Physiology, and Internal Medicine, Department of Veterans Affairs Medical Center, Dallas, Texas, 75216, and the University of Texas Southwestern Medical Center, Dallas, Texas, 75235; Neuromuscular Unit and Department of Clinical Physiology, Linkiping University Hospital, S-58185 Linklping, Sweden; the Departments ofClinical Chemistry and Clinical Physiology, Karolinska Institute/Huddinge University Hospital, S-14186 Huddinge, Sweden; and the Department ofMedical Genetics, Oregon Health Sciences University, Portland, Oregon 97201 Abstract 1206.) Key words: succinate dehydrogenase - aconitase * com- plex II * exercise We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, Introduction dyspnea, and cardiac palpitations with superimposed episodes of increased muscle fatigability and Larsson et al. (1) and Linderholm et al. (2) described 14 pa- lasting days to weeks tients from five families in northern Sweden with a history of weakness associated with painful muscle swelling and pigmen- lifelong, severe exercise intolerance punctuated by episodes of turia. Cycle exercise testing revealed low maximal oxygen up- muscle fatigability, weakness, and muscle swelling in sedentary men = 39±5) with increased take (12 ml/min per kg; healthy association with myoglobinuria. Investigation of seven of these exaggerated increases in venous lactate and pyruvate in relation cardiac and peripheral vascular catheterization to oxygen uptake (V02) but low lactate/pyruvate ratios in max- patients using was character- during cycle exercise revealed low oxidative capacity and low imal exercise. The severe oxidative limitation maximal muscle oxygen extraction as indicated by low sys- ized by impaired muscle oxygen extraction indicated by subnor- The car- oxygen difference (a-v 02 diff) in temic and femoral arteriovenous oxygen differences. mal systemic arteriovenous diac output response to exercise was greatly exaggerated or "hy- maximal exercise (patient = 4.0 ml/dl, normal men = and as normal and perkinetic" relative to exercise workload metabolic rate, 16.7±2.1) despite oxygen carrying capacity Hgb- evident clinically by marked tachycardia and a sense ofcardiac 02 PSO. In contrast maximal oxygen delivery (cardiac output, men patient palpitations induced by trivial exercise. The biochemical basis Q) was high compared to sedentary healthy (Q..: of this disorder has not been fully characterized but Linder- = 303 ml/min per kg, normal men 238±36) and the slope of Q holm et al. recently reported finding reduced muscle succinate increase in relative to V02 (i.e., A&Q/AVO2) from rest to a = dehydrogenase in an affected patient (3). We evaluated 22-yr- exercise was exaggerated (A&Q/AVO2, patient 29, normal old man from a similar coastal area of northern Sweden with = the normal approxi- men 4.7±0.6) indicating uncoupling of an identical clinical history and similar exercise pathophysiol- mately 1:1 relationship between oxygen delivery and utilization ogy. Biochemical investigation of skeletal muscle revealed im- in dynamic exercise. Studies of isolated skeletal muscle mito- paired oxidation of succinate, deficiency of succinate dehydro- chondria in our patient revealed markedly impaired succinate genase activity, and reduced levels of the 30-kD (iron-sulfur) oxidation with normal glutamate oxidation implying a meta- and 13.5-kD proteins of complex II (succinate ubiquinone oxi- bolic defect at the level of complex II of the mitochondrial doreductase, EC 1.3.5.1). This defect in complex II was asso- respiratory chain. A defect in Complex H in skeletal muscle ciated with deficiency ofmitochondrial aconitase assessed enzy- was confirmed by the finding of deficiency of succinate dehydro- matically and immunologically and with abnormal deposition genase as determined histochemically and biochemically. Im- of iron in the patient's mitochondria. We postulate that the munoblot analysis showed low amounts of the 30-kD (iron-sul- abnormal metabolic and circulatory responses to exercise in fur) and 13.5-kD proteins with near normal levels of the 70-kD this condition relate to severely impaired muscle oxidative protein of complex II. Deficiency of succinate dehydrogenase phosphorylation due to a low rate of generation of NADH by was associated with decreased levels of mitochondrial aconi- the tricarboxylic acid (TCA)1 cycle attributable to deficiency of tase assessed enzymatically and immunologically whereas activ- succinate dehydrogenase and aconitase activities. ities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consis- Methods tent with the hypothesis that this defect impairs muscle oxida- tive metabolism by limiting the rate of NADH production by Clinical history the tricarboxylic acid cycle. (J. Clin. Invest. 1991. 88:1197- The patient was a 22-yr-old man with lifelong exercise intolerance marked by premature fatigue. He recalled that he could never walk as long or as far as other children. Exercise was limited by the rapid devel- Address correspondence to Ronald G. Haller, M. D., Neurology Ser- vice (127), Veterans Affairs Medical Center, 4500 South Lancaster, Dallas, TX 75216. Dr. Lewis' current address is Department of Health 1. Abbreviations used in this paper: a-v °2 diff, arteriovenous oxygen Sciences, Boston University, 635 Commonwealth Avenue, Boston, difference; L/P, ratio of venous lactate to venous pyruvate; Po, oxygen MA 02215. tension at which 50% of hemoglobin is saturated with oxygen; Q, car- Received for publication 7 February 1990 and in revised form 11 diac output; AQ/AVO2, increase in cardiac output relative to the in- June 1991. crease in oxygen uptake from rest to exercise; RER, respiratory ex- change; SDH, succinate dehydrogenase; TCA, tricarboxylic acid; The Journal of Clinical Investigation, Inc. VCO2, carbon dioxide production; VE, ventilation; V02, oxygen up- Volume 88, October 1991, 1197-1206 take. Exercise Pathophysiology in Muscle Succinate Dehydrogenase Deficiency 1197 opment of heaviness, weakness, and sometimes aching of active mus- were determined in perchloric acid extracts of whole blood (7) and the cles. In addition, trivial exertion provoked a rapid heartbeat and a sense lactate/pyruvate ratio (L/P) was calculated. In an additional experi- of dyspnea. Exertional fatigue most prominently involved his legs and ment separated by an 11-yr interval from other testing, a femoral he felt that his arms were relatively spared. In the legs, the calves were venous catheter was placed for sampling of femoral venous Po2 and °2 most prone to aching and weakness and usually there was some degree saturation, lactate, and pyruvate at rest and during maximal cycle exer- of persistent calf tenderness to palpation. In recent years he has been cise. Results were compared to eight healthy Swedish men (8). aware of prominent calf hypertrophy. Morphological and biochemical evaluation of muscle. An open The patient also experienced episodes of significant worsening of biopsy ofthe rectus femoris muscle was performed under local anesthe- his muscle symptoms which occurred about two times per year and sia for histopathological and biochemical determinations. Portions of typically lasted for 1-2 wk. These periods were characterized by in- the biopsy were