Influence of erythrocyte oxygenation and intravascular ATP on resting and exercising skeletal muscle blood flow in humans with mitochondrial myopathy

Oxygen (O2) extraction is impaired in exercising skeletal muscle of humans with mutations of mitochondrial DNA (mtDNA), but the muscle hemodynamic response to exercise has never been directly investigated. This study sought to examine the extent to which human skeletal muscle perfusion can increase without reductions in blood oxygenation and to determine whether erythrocyte O2 off-loading and related ATP vascular mechanisms are impaired in humans with mutations of mtDNA. Leg vascular hemodynamic, oxygenation and ATP were investigated in ten patients with mtDNA mutations and ten matched healthy control subjects: 1) at rest during normoxia, hypoxia, hyperoxia and intra-femoral artery ATP infusion, and 2) during passive and dynamic one-legged knee-extensor exercises. At rest, blood flow (LBF), femoral arterial and venous blood oxygenation and plasma ATP were similar in the two groups. During dynamic exercise, LBF and vascular conductance increased 9–10 fold in the patients despite erythrocyte oxygenation and leg O2 extraction remained unchanged (p < 0.01). In the patients, workload-adjusted LBF was 28% to 62% higher during submaximal- and maximal exercises and was associated with augmented plasma ATP. The appropriate hemodynamic adjustments during severe hypoxia and ATP infusion suggest that erythrocyte O2 off-loading and related ATP vascular mechanisms are intact in patients with mtDNA mutations. Furthermore, greater increase in plasma ATP and LBF at a given metabolic demand in the patients, in concert with unchanged oxyhemoglobin, suggest that erythrocyte O2 off-loading is not obligatory for the exercise-induced increase in blood flow and intravascular ATP concentration.

► Blood flow to contracting skeletal muscle with mtDNA mutations is 62% increased.
► The exaggerated limb blood flow occurs in concert with unaltered venous oxygenation.
► Erythrocyte and related vascular mechanisms are intact in mitochondrial patients.
► High ATP levels could mediate the augmented O2 delivery in mitochondrial patients.
► Erythrocyte O2 offloading is not obligatory for elevation of intravascular ATP.