Convective O2 Transport and Skeletal Muscle Mitochondrial Function in Peripheral Arterial Disease Patients

Abstract

Peripheral arterial disease (PAD) is characterized by insufficient oxygen (O2) supply secondary to reduced blood flow, which provides a unique model to assess the effects of chronic limited O2 delivery on skeletal muscle oxidative capacity. Previous evidence, collected in vivo, suggests that reductions in peak mitochondrial ATP synthesis rates (Vmax) in the skeletal muscle of PAD patients can be attributed to the disease-related impairment in O2 supply, while in vitro assessments have revealed deficits in mitochondrial respiration (JO2) despite ample O2 supply, thereby alluding to defective mitochondrial function as a potential factor in PAD pathology. PURPOSE: To determine the extent to which O2 supply and intrinsic mitochondrial deficits play a role in PAD by combining both in vivo and in vitro assessments of skeletal muscle mitochondrial function. METHODS: Phosphorus magnetic resonance spectroscopy (31P-MRS) and Doppler ultrasound were combined to examine the effect of superimposing reactive hyperemia (RH), induced by a period of brief ischemia during the last 30s of exercise, compared to free-flow conditions (FF) on O2 delivery and Vmax in the calf muscle of 10 PAD patients and 10 physical activity-matched healthy controls (HC). Complex I and II, State 3 JO2 was assessed in vitro on muscle biopsies from the medial gastrocnemius. RESULTS: RH significantly increased post-exercise limb blood flow in HC (FF: 874 ± 271; RH: 1204 ± 284 ml.min-1, P<0.05) with a corresponding improvement in Vmax (FF: 14 ± 3; RH: 19 ± 4 mM.min-1, P<0.05). In contrast, in PAD patients there were no differences in initial post-exercise limb blood flow (FF: 379 ± 136; RH: 441 ± 112 ml.min-1) or Vmax (FF: 11 ± 4; RH: 11 ± 3 mM.min-1). Interestingly, State 3 JO2 assessed in vitro was not different between HC and PAD patients (HC: 24 ± 7; PAD: 25 ± 5 pmol/sec/mg). CONCLUSION: As there was no evidence of an intrinsic mitochondrial deficit in PAD patients, assessed in vitro with adequate O2, observations in vivo that post-exercise blood flow was unable to be augmented and metabolic capacity was attenuated strongly implicates O2 supply as the factor limiting mitochondrial function in PAD. Interestingly, these data reveal that O2 supply in vivo also limits metabolic function in HC, but, in this case, vascular function demonstrates greater plasticity.