Oxygen availability and skeletal muscle oxidative capacity in patients with peripheral artery disease: implications from in vivo and in vitro assessments

Abstract

Evidence suggests that the peak skeletal muscle mitochondrial ATP synthesis rate ( V) in patients with peripheral artery disease (PAD) may be attenuated due to disease-related impairments in O supply. However, in vitro assessments suggest intrinsic deficits in mitochondrial respiration despite ample O availability. To address this conundrum, Doppler ultrasound, near-infrared spectroscopy, phosphorus magnetic resonance spectroscopy, and high-resolution respirometry were combined to assess convective O delivery, tissue oxygenation, V, and skeletal muscle mitochondrial capacity (complex I + II, state 3 respiration), respectively, in the gastrocnemius muscle of 10 patients with early stage PAD and 11 physical activity-matched healthy control (HC) subjects. All participants were studied in free-flow control conditions (FF) and with reactive hyperemia (RH) induced by a period of brief ischemia during the last 30 s of submaximal plantar flexion exercise. Patients with PAD repeated the FF and RH trials under hyperoxic conditions (FF + 100% O and RH + 100% O). Compared with HC subjects, patients with PAD exhibited attenuated O delivery at the same absolute work rate and attenuated tissue reoxygenation and V after relative intensity-matched exercise. Compared with the FF condition, only RH + 100% O significantly increased convective O delivery (~44%), tissue reoxygenation (~54%), and V (~60%) in patients with PAD ( P < 0.05), such that V was now not different from HC subjects. Furthermore, there was no evidence of an intrinsic mitochondrial deficit in PAD, as assessed in vitro with adequate O. Thus, in combination, this comprehensive in vivo and in vitro investigation implicates O supply as the predominant factor limiting mitochondrial oxidative capacity in early stage PAD. NEW & NOTEWORTHY Currently, there is little accord as to the role of O availability and mitochondrial function in the skeletal muscle dysfunction associated with peripheral artery disease. This is the first study to comprehensively use both in vivo and in vitro approaches to document that the skeletal muscle dysfunction associated with early stage peripheral artery disease is predominantly a consequence of limited O supply and not the impact of an intrinsic mitochondrial defect in this pathology.

The Rise of Mitochondria in Peripheral Arterial Disease Physiopathology: Experimental and Clinical Data

“…Oxygraphy measurements in PAD patients revealed significantly altered respiratory activity, notably of complexes I, III and IV, and of the acceptor control ratio [27][28][29][30]. Interestingly, more recent studies reported no difference in the mitochondrial respiration rate between PAD patients and healthy controls, despite alterations in O 2 delivery, tissue-reoxygenation and ATP synthesis rate during exercise [31,32]. These conflicting findings could be explained by disparities in disease severity.…”

Skeletal muscle performance in metabolic disease: Microvascular or mitochondrial limitation or both?

“…As previously stated skeletal muscle performance is limited by either oxygen supply to or oxygen consumption through mitochondrial oxidative phosphorylation (MOP). Determining whether oxygen supply (limitations previously described) or mitochondrial respiratory capacity limits MOP can be performed in a broad array of metabolic (dys)functional states . In healthy human subjects, one can test where these limits arise with a simple experiment by altering arterial oxygen concentrations and measuring oxidative phosphorylation rate following exercise perturbations.…”

“…Conversely, if increasing oxygen concentration also increases MOP rates it must mean oxygen availability is limiting the system. Using this simple experimental perturbation by breathing gases of differing oxygen concentrations Richardson et al were able to show that mitochondria were the limiting factor in healthy human subjects while oxygen supply was the limiting factor in exercise trained and peripheral arterial disease patients . These studies support the contention that not only can limitations be measured during dynamic exercise, but alterations can be made to reveal the true determinant of muscle respiratory capacity.…”

The alterations effects in phosphorus of erythropoietin and U-74389G

“…Gruson, et al claimed [8] that the increase of ibroblast growth factor 23 (FGF-23), a key hormone for the regulation of the phosphorus homeostasis, participates to cardiac hypertrophy and remodeling in heart failure. Hart, et al repeated [9] the free-low control conditions (FF) and reactive hyperemia (RH) trials under hyperoxic conditions (FF + 100% O 2 and RH + 100% O 2 ) in skeletal gastrocnemius muscle of patients with peripheral artery disease. Anselmo, et al attenuated [10] IR-induced renal changes, with reduction of plasmatic phosphorus as well as reducing kidney expression of iNOS, nitrotyrosine and macrophage in lux after pretreatment with 75 mg of Brazil nuts.…”