Pesta 2011Abstract Mitochondrial Medicine-Diagnosis
|Pesta D, Wiethuechter A, Karall D, Schocke M, Gnaiger E (2011) Functional mitochondrial diagnosis in a patient suffering from sudden exercise intolerance. Abstract Mitochondrial Medicine Chicago.|
Link: UMDF 2011
A 28-year-old former amateur cyclist demonstrated a sudden exercise intolerance and impairment in muscle function since March 2008 without clinical explanation. The main symptom was a decreased ergometric aerobic capacity by 50%. A specific defect of mitochondrial glutamate dehydrogenase (GDH) was indicated by lack of ADP stimulation in the presence of glutamate and subsequent rescue of respiration after addition of malate.
• Keywords: Glutamate dehydrogenase
Stress:Mitochondrial disease Organism: Human
Preparation: Permeabilized tissue, Homogenate Enzyme: TCA cycle and matrix dehydrogenases
Coupling state: OXPHOS
A 28-year-old former amateur cyclist demonstrated a sudden exercise intolerance and impairment in muscle function since March 2008 without clinical explanation. The main symptom was a decreased ergometric aerobic capacity by 50%.
A small needle biopsy sample was obtained from the patient´s M. vastus lateralis to assess mitochondrial function by high-resolution respirometry using substrate-uncoupler-inhibitor titration (SUIT) protocols on permeabilized fibers [1,2]. The patient performed an in-vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS) test of the quadriceps muscles during dynamic leg-extension exercise  and a pelvic-leg angiography (0.2 mL/kg Multihance, Bracco, Italy). Additional metabolic investigations were performed on blood, blood gas and urine smaples.
A specific defect of mitochondrial glutamate dehydrogenase (GDH) was indicated by lack of ADP stimulation in the presence of glutamate and subsequent rescue of respiration after addition of malate. Except for a low CI/CII flux ratio, mass-specific respirometric fluxes were low but generally comparable to healthy controls, explaining a decreased exercise capacity but not the diseased condition of the patient. Phosphorylation capacity was apparently normal as indicated by an unsuspicious PCr recovery time (t=40 s). This is in line with a P/E ratio of ~0.9 and normal coupling control of mitochondrial respiration. Although the angiography did not indicate any stenosis in the common iliac arteries, an atypical initial increase from c. 4 to 10 mM was observed in inorganic phosphate (Pi) during mild exercise performed with an MR-suitable ergometer. Metabolic investigations were normal (acylcarnitine profile, amino acid in plasma and urine, organic acids in urine, lactate, glucose, blood gas analysis and creatine kinase as well as liver function tests).
Our data indicate a reduced Pi-buffering capacity in the muscle resulting in accumulation of Pi from baseline to c. 10 mM. Whereas the phosphorylation system and pyruvate-supported respiration were unimpaired, we found a specific defect of mitochondrial GDH and a low CI/CII flux ratio. Taken together, these data may explain the exercise intolerance in the patient, with clinical symptoms possibly delayed by a physically active life style.
Supported by OeNB Jubilaeumsfond Austria, project 13476; contribution to Mitofood COST Action FAO602, and MitoCom_O2k-Fluorometer Network Tyrol.
- Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837–45.
- Pesta D, Gnaiger E (2012) High-resolution respirometry. OXPHOS protocols for human cells and permeabilized fibres from small biopsies of human muscle. Methods Mol Biol 810:25-58.
- Schocke MF, Esterhammer R, Arnold W, Kammerlander C, Burtscher M, Fraedrich G, et al (2005) High-energy phosphate metabolism during two bouts of progressive calf exercise in humans measured by phosphorus-31 magnetic resonance spectroscopy. Eur J Appl Physiol 93:469-79.