Deficiency of skeletal muscle succinate dehydrogenase and aconitase: Pathophysiology of exercise in a novel human muscle oxidative defect

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 HgbO₂ P₅₀. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Q_max, patient = 303 ml/min per kg, normal men 238 ± 36) and the slope of increase in Q relative to VO₂ (i.e., ΔQ/ΔVO₂) from rest to exercise was exaggerated (ΔQ/ΔVO₂, 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 the level of complex II of the mitochondrial respiratory chain. A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle.