Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
Level 4 - case-series / case-control
Single patient case study with physiological and biochemical investigations.
PubMed 1918374 · doi:10.1172/JCI115422
What was done
Physiological and biochemical evaluations were conducted in a 22-year-old man presenting with lifelong exercise intolerance, exertional muscle fatigue, dyspnea, palpitations, muscle swelling, and pigmenturia. The patient underwent cycle exercise testing measuring maximal oxygen uptake, blood lactate and pyruvate levels, systemic arteriovenous oxygen difference, and cardiac output. Muscle biopsy tissue was analyzed for mitochondrial oxidation rates, complex II subunit expression via immunoblotting, and enzyme activities across the tricarboxylic acid (TCA) cycle and respiratory chain.
What was found
Cycle testing revealed markedly low maximal oxygen uptake (12 ml/min/kg vs. 39 ± 5 in healthy controls) and severely impaired maximal systemic arteriovenous oxygen difference (4.0 ml/dl vs. 16.7 ± 2.1), despite elevated maximal cardiac output (303 ml/min/kg vs. 238 ± 36) and an exaggerated cardiac output-to-oxygen consumption response slope (delta Q/delta VO2 = 29 vs. 4.7 ± 0.6). Venous lactate and pyruvate increased abnormally relative to oxygen uptake with low lactate/pyruvate ratios. Isolated muscle mitochondria showed impaired succinate oxidation with intact glutamate oxidation, deficient succinate dehydrogenase activity, reduced complex II 30-kD and 13.5-kD subunit levels, and decreased mitochondrial aconitase activity, alongside elevated activities of other TCA cycle enzymes.
Why it matters
This study defines the pathophysiology of a rare metabolic myopathy involving combined succinate dehydrogenase and aconitase deficiency. It demonstrates that impaired TCA cycle NADH generation drastically limits peripheral oxygen extraction during dynamic exercise, triggering a compensatory hyperdynamic cardiovascular response.
Limits
The study is restricted to a single patient (n = 1), preventing generalization across broader populations. The abstract does not report genetic sequencing data identifying the underlying molecular mutation, nor does it assess longitudinal disease progression or therapeutic responses.
Cited by
- supports Patients with mitochondrial myopathies exhibit an exaggerated cardiac output response to exercise, increasing cardiac output by 10 to 20 liters per liter of oxygen uptake compared to normal values of around 5 liters.