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

Ronald G. Haller, K. G. Henriksson, 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, Steven F. Lewis

Research output: Contribution to journalArticle

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Abstract

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 (Qmax, 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.

Original languageEnglish (US)
Pages (from-to)1197-1206
Number of pages10
JournalJournal of Clinical Investigation
Volume88
Issue number4
StatePublished - 1991

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Aconitate Hydratase
Succinate Dehydrogenase
Skeletal Muscle
Exercise
Oxygen
Muscles
Citric Acid Cycle
Pyruvic Acid
Lactic Acid
Muscle Mitochondrion
Muscle Fatigue
Muscle Weakness
Conservation of Natural Resources
Succinic Acid
Electron Transport
Sulfur
Cardiac Output
NAD
Dyspnea
Glutamic Acid

Keywords

  • Aconitase
  • Complex II
  • Exercise
  • Succinate dehydrogenase

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Deficiency of skeletal muscle succinate dehydrogenase and aconitase : Pathophysiology of exercise in a novel human muscle oxidative defect. / Haller, Ronald G.; Henriksson, K. G.; Jorfeldt, Lennart; Hultman, Eric; Wibom, Rolf; Sahlin, Kent; Areskog, Nils Holger; Gunder, Marguerite; Ayyad, Karen; Blomqvist, C. Gunnar; Hall, Robin E.; Thuillier, Phillippe; Kennaway, Nancy G.; Lewis, Steven F.

In: Journal of Clinical Investigation, Vol. 88, No. 4, 1991, p. 1197-1206.

Research output: Contribution to journalArticle

Haller, RG, Henriksson, KG, Jorfeldt, L, Hultman, E, Wibom, R, Sahlin, K, Areskog, NH, Gunder, M, Ayyad, K, Blomqvist, CG, Hall, RE, Thuillier, P, Kennaway, NG & Lewis, SF 1991, 'Deficiency of skeletal muscle succinate dehydrogenase and aconitase: Pathophysiology of exercise in a novel human muscle oxidative defect', Journal of Clinical Investigation, vol. 88, no. 4, pp. 1197-1206.
Haller, Ronald G. ; Henriksson, K. G. ; Jorfeldt, Lennart ; Hultman, Eric ; Wibom, Rolf ; Sahlin, Kent ; Areskog, Nils Holger ; Gunder, Marguerite ; Ayyad, Karen ; Blomqvist, C. Gunnar ; Hall, Robin E. ; Thuillier, Phillippe ; Kennaway, Nancy G. ; Lewis, Steven F. / Deficiency of skeletal muscle succinate dehydrogenase and aconitase : Pathophysiology of exercise in a novel human muscle oxidative defect. In: Journal of Clinical Investigation. 1991 ; Vol. 88, No. 4. pp. 1197-1206.
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AU - Hultman, Eric

AU - Wibom, Rolf

AU - Sahlin, Kent

AU - Areskog, Nils Holger

AU - Gunder, Marguerite

AU - Ayyad, Karen

AU - Blomqvist, C. Gunnar

AU - Hall, Robin E.

AU - Thuillier, Phillippe

AU - Kennaway, Nancy G.

AU - Lewis, Steven F.

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N2 - 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 (Qmax, 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.

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