Succinate recovers mitochondrial oxygen consumption in septic rat skeletal muscle.
OBJECTIVE
Mitochondrial dysfunction, particularly affecting complex I of the respiratory chain, could play a fundamental role in the development of multiple organ failure during sepsis. Increasing electron flow through complex II by addition of succinate may improve mitochondrial oxygen utilization and thus adenosine triphosphate production.


METHODS
Ex vivo animal study.


METHODS
University research laboratory.


METHODS
Male adult Wistar rats.


METHODS
Fecal peritonitis was induced in conscious, fluid-resuscitated, hemodynamically-monitored rats. Sham-operation and naïve animals acted as controls. At 48 hrs, clinical severity was graded. Soleus muscle was taken for measurement of mitochondrial complex activities and oxygen consumption. The effect of glutamate plus malate (complex I substrates) and succinate (complex II substrate) on mitochondrial respiration was assessed.


RESULTS
In the presence of glutamate plus malate, mitochondrial oxygen consumption was abnormally low in skeletal muscle tissue from moderately-to-severely septic animals as compared with naïve and sham-operation controls (both p < .01). On addition of succinate, mitochondrial respiration was augmented in all groups, particularly in moderately-to-severely septic animals (39% +/- 6% increase) as compared with naïve (11% +/- 5%; p < .01) and sham-operation controls (10% +/- 5%; p < .01). In the presence of succinate, mitochondrial oxygen consumption was similar between the groups.


CONCLUSIONS
Succinate increases mitochondrial oxygen consumption in ex vivo skeletal muscle taken from septic animals, bypassing the predominant inhibition occurring at complex I. This warrants further exploration in vivo as a putative therapeutic modality.
Protti
Alessandro
A
Bloomsbury Institute of Intensive Care Medicine, Wolfson Institute for Biomedical Research, and Department of Medicine, University College London, London, UK.
Carré
Jane
J
Frost
Matthew T
MT
Taylor
Valerie
V
Stidwill
Raymond
R
Rudiger
Alain
A
Singer
Mervyn
M
D000818:Animals; D008293:Malates / Q000494:pharmacology; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D010538:Peritonitis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism*; D013386:Succinates / Q000494:pharmacology*
D008293:Malates; D013386:Succinates