Cookies help us deliver our services. By using our services, you agree to our use of cookies. More information

Difference between revisions of "Pesta 2011Abstract Mitochondrial Medicine-Diagnosis"

From Bioblast
(Created page with "{{Publication |title=Pesta D, Hoppel F, Macek C, Messner H, Faulhaber M, Kobel C, Parson W, Burtscher M, Schocke M, Gnaiger E (2011) Mitochondrial improvements after strength, en...")
 
Line 1: Line 1:
{{Publication
{{Publication
|title=Pesta D, Hoppel F, Macek C, Messner H, Faulhaber M, Kobel C, Parson W, Burtscher M, Schocke M, Gnaiger E (2011) Mitochondrial improvements after strength, endurance, and intermittend hypoxic training in sedentary humans. A respiratory study on permeabilized muscle fibres. Abstract Mitochondrial Medicine Chicago.  
|title=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.
|info=[http://www.umdf.org/symposium UMDF 2011]
|info=[http://www.umdf.org/symposium UMDF 2011]
|authors=Pesta D, Hoppel F, Macek C, Messner H, Faulhaber M, Kobel C, Parson W, Burtscher M, Schocke M, Gnaiger E
|authors=Pesta D, Wiethuechter A, Karall D, Schocke M, Gnaiger E
|year=2011
|year=2011
|journal=Abstract
|journal=Abstract
|abstract=The main finding was a significant increase (''P''<0.05) of lipid oxidation capacity in all groups, after normoxic (255% ETN, ''N''=8 and 238% STN, ''N''=3), and hypoxic endurance and strength training (198% ET, ''N''=7 and 198% ST, ''N''=7).
|abstract=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
|mipnetlab=AT Innsbruck Gnaiger E, AT Innsbruck Burtscher M
|mipnetlab=AT Innsbruck Gnaiger E, AT Innsbruck Burtscher M
}}
}}
{{Labeling
{{Labeling
|instruments=Oxygraph-2k
|instruments=Oxygraph-2k
|injuries=Hypoxia
|injuries=Mitochondrial Disease; Degenerative Disease and Defect
|organism=Human
|organism=Human
|tissues=Skeletal Muscle
|tissues=Skeletal Muscle
|preparations=Permeabilized Cell or Tissue; Homogenate
|preparations=Permeabilized Cell or Tissue; Homogenate
|topics=Respiration; OXPHOS; ETS Capacity, Mitochondrial Biogenesis; Mitochondrial Density
|enzymes=TCA Cycle and Matrix Dehydrogenases
|additional=Training
|topics=Respiration; OXPHOS; ETS Capacity
}}
}}
==Full abstract==
==Full abstract==


Endurance and strength training are established as two distinct training modalities, increasing either mitochondrial density or extension of myofibrillar units. Recent research, however, suggests that mitochondrial biogenesis can be induced by both strength and conventional endurance training.  
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%.


In order to test the training-specific hypothesis, mitochondrial respiratory function was studied by high-resolution respirometry in response to a 10-weeks training program using human permeablized muscle fibers from 26 sedentary volunteers undergoing either endurance or strength training in normoxia (ETN, STN; FiO2=21%) or hypoxia (ETH, STH; FiO2=13.5%). Biopsies were taken from the m. vastus lateralis and all volunteers performed a cycle-ergometric incremental exercise test under normoxia to determine their ''V''O2,max before and after training.
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 [3] and a pelvic-leg angiography (0.2 mL/kg Multihance, Bracco, Italy). Additional metabolic investigations were performed on blood, blood gas and urine smaples.


The main finding was a significant increase (''P''<0.05) of lipid oxidation capacity in all groups, after normoxic (255% ETN, ''N''=8 and 238% STN, ''N''=3), and hypoxic endurance and strength training (198% ET, ''N''=7 and 198% ST, ''N''=7). This increase was related mainly to a change in mitochondrial density, reflected by the tissue-specific respiratory capacity with [[Complex I]]- and [[Complex II]]-related substrates. Although this index of mitochondrial density increased significantly in the ETN group only (''P''<0.05), the trend was identical in all groups, without significant increases in mtDNA contents. Qualitative mitochondrial changes, however, were significant (''P''<0.01) in all training regimes, indicated by the increased relative capacity for lipid oxidation and increased coupling of oxidative phosphorylation.
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).


Exercise training leads to several alterations of mitochondrial function regardless of normoxic or hypoxic exposure. Unexpectedly, key mitochondrial adaptations were similar in the endurance and strength training group, which reflects a different response to training in sedentary versus athletic subjects. Beyond these novel results on specific training regimes, the present study on sports science establishes a data base on healthy but sedentary subjects, as valuable controls for evaluation of functional mitochondrial defects in patients.
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 ''[[MitoCom]] Network Tyrol''.
Supported by OeNB Jubilaeumsfond Austria, project 13476; contribution to Mitofood COST Action FAO602, and ''[[MitoCom]] Network Tyrol''.
 
# [[Gnaiger_2009_IJBCB|Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int. J. Biochem. Cell Biol. 41: 1837–1845]].
# [[Pesta_2011_Protocols|Pesta D, Gnaiger E (2011) High-resolution respirometry. OXPHOS protocols for human cell cultures and permeabilized fibres from small biopsies of human muscle. In: Mitochondrial bioenergetics: methods and protocols (Series Editor: Sir John Walker), edited by Carlos Palmeira and António Moreno]].
# 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: 469-479.

Revision as of 20:40, 26 October 2011

Publications in the MiPMap
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.

» UMDF 2011

Pesta D, Wiethuechter A, Karall D, Schocke M, Gnaiger E (2011) Abstract

Abstract: 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

O2k-Network Lab: AT Innsbruck Gnaiger E, AT Innsbruck Burtscher M


Labels:

Stress:Mitochondrial Disease; Degenerative Disease and Defect"Mitochondrial Disease; Degenerative Disease and Defect" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property.  Organism: Human  Tissue;cell: Skeletal Muscle"Skeletal Muscle" is not in the list (Heart, Skeletal muscle, Nervous system, Liver, Kidney, Lung;gill, Islet cell;pancreas;thymus, Endothelial;epithelial;mesothelial cell, Blood cells, Fat, ...) of allowed values for the "Tissue and cell" property.  Preparation: Permeabilized Cell or Tissue; Homogenate"Permeabilized Cell or Tissue; Homogenate" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property.  Enzyme: TCA Cycle and Matrix Dehydrogenases"TCA Cycle and Matrix Dehydrogenases" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property.  Regulation: Respiration; OXPHOS; ETS Capacity"Respiration; OXPHOS; ETS Capacity" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property. 


HRR: Oxygraph-2k 


Full abstract

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 [3] 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 Network Tyrol.

  1. Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int. J. Biochem. Cell Biol. 41: 1837–1845.
  2. Pesta D, Gnaiger E (2011) High-resolution respirometry. OXPHOS protocols for human cell cultures and permeabilized fibres from small biopsies of human muscle. In: Mitochondrial bioenergetics: methods and protocols (Series Editor: Sir John Walker), edited by Carlos Palmeira and António Moreno.
  3. 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: 469-479.