title: Abnormal mitochondrial respiration in skeletal muscle in patients with peripheral arterial disease.
abstract: OBJECTIVE
  Discrete morphologic, enzymatic and functional changes in skeletal muscle mitochondria have been demonstrated in patients with peripheral arterial disease (PAD). We examined mitochondrial respiration in the gastrocnemius muscle of nine patients (10 legs) with advanced PAD and in nine control patients (nine legs) without evidence of PAD.
  
  
  METHODS
  Mitochondrial respiratory rates were determined with a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles. Muscle samples were obtained from the anteromedial aspect of the gastrocnemius muscle, at a level 10 cm distal to the tibial tuberosity. Mitochondria respiratory rate, calculated as nanoatoms of oxygen consumed per minute per milligram of noncollagen protein, were measured at baseline (V(0)), after addition of substrates (malate and glutamate; (V(SUB)), after addition of adenosine diphosphate (ADP) (V(ADP)), and finally, after adenine nucleotide translocase inhibition with atractyloside (V(AT)). The acceptor control ratio, a sensitive indicator of overall mitochondrial function, was calculated as the ratio of the respiratory rate after the addition of ADP to the respiratory rate after adenine nucleotide translocase inhibition with atractyloside (V(ADP)/ V(AT)).
  
  
  RESULTS
  Respiratory rate in muscle mitochondria from patients with PAD were not significantly different from control values at baseline (0.31 +/- 0.06 vs 0.55 +/- 0.12; P =.09), but V(sub) was significantly lower in patients with PAD compared with control subjects (0.43 +/- 0.07 vs 0.89 +/- 0.20; P <.05), as was V(ADP) (0.69 +/- 0.13 vs 1.24 +/- 0.20; P <.05). Respiratory rates after atractyloside inhibition in patients with PAD were no different from those in control patients (0.47 +/- 0.07 vs 0.45 +/- P =.08). Compared with control values, mitochondria from patients with PAD had a significantly lower acceptor control ratio (1.41 +/- 0.10 vs 2.90 +/- 0.20; P <.001).
  
  
  CONCLUSIONS
  Mitochondrial respiratory activity is abnormal in lower extremity skeletal muscle in patients with PAD. When considered in concert with the ultrastructural and enzymatic abnormalities previously documented in mitochondria of chronically ischemic muscle, these data support the concept of defective mitochondrial function as a pathophysiologic component of PAD.
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, 983280 Nebraska Medical Center, Omaha, NE 68198-3280, USA. ipipinos@unmc.edu
authors.forename: Iraklis I
authors.initials: II
authors.lastname: Pipinos
authors.forename: Victor G
authors.initials: VG
authors.lastname: Sharov
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Shepard
authors.forename: Petros V
authors.initials: PV
authors.lastname: Anagnostopoulos
authors.forename: Asterios
authors.initials: A
authors.lastname: Katsamouris
authors.forename: Anastasia
authors.initials: A
authors.lastname: Todor
authors.forename: Konstantinos A
authors.initials: KA
authors.lastname: Filis
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000368:Aged; D001278:Atractyloside / Q000494:pharmacology; D001706:Biopsy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007383:Intermittent Claudication / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism*; D008293:Malates / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors; D018482:Muscle, Skeletal / Q000378:metabolism*; D010101:Oxygen Consumption
chemical_list: D004791:Enzyme Inhibitors; D008293:Malates; D001278:Atractyloside; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; C030298:malic acid; D000226:Mitochondrial ADP, ATP Translocases