Impaired Tissue Oxygenation in Metabolic Syndrome Requires Increased Microvascular Perfusion Heterogeneity

Abstract

Metabolic syndrome (MS) in obese Zucker rats (OZR) is associated with impaired skeletal muscle performance and blunted hyperemia. Studies suggest that reduced O2 diffusion capacity is required to explain compromised muscle performance and that heterogeneous microvascular perfusion distribution is critical. We modeled tissue oxygenation during muscle contraction in control and OZR skeletal muscle using physiologically realistic relationships. Using a network model of Krogh cylinders with increasing perfusion asymmetry and increased plasma skimming, we predict increased perfusion heterogeneity and decreased muscle oxygenation in OZR, with partial recovery following therapy. Notably, increasing O2 delivery had less impact on VO2 than equivalent decreases in O2 delivery, providing a mechanism for previous empirical work associating perfusion heterogeneity and impaired O2 extraction. We demonstrate that increased skeletal muscle perfusion asymmetry is a defining characteristic of MS and must be considered to effectively model and understand blood-tissue O2 exchange in this model of human disease.

Dissociation of local and global skeletal muscle oxygen transport metrics in type 2 diabetes

“…Distribution of blood flow is more spatially heterogeneous in the obese Zucker rat model of type 2 diabetes, and this perfusion heterogeneity is associated with impaired oxygen uptake. 14,15,24,25 Simulation studies reveal that heterogeneous perfusion results in impaired muscle oxygenation on average, because over-perfused vessels cannot fully compensate for under-perfused vessels. 15,26–28 By definition, heterogeneous perfusion not resulting from heterogeneous tissue demand would result in flow/VO 2 mismatch.…”

“…14,15,24,25 Simulation studies reveal that heterogeneous perfusion results in impaired muscle oxygenation on average, because over-perfused vessels cannot fully compensate for under-perfused vessels. 15,26–28 By definition, heterogeneous perfusion not resulting from heterogeneous tissue demand would result in flow/VO 2 mismatch. Moreover, these effects would influence skeletal muscle deoxygenation/oxygenation even in cases of normal bulk blood flow and local recruitment of microvascular blood volume/hematocrit.…”

“…10 There are several plausible mechanisms that may contribute to impaired oxygen delivery to skeletal muscle in type 2 diabetes, including reduced capillary density, 11 reduced blood flow, 12 loss of capillary perfusion, 13 and heterogeneous distribution of blood flow. 14,15 Although each of these possible contributors has been previously noted, contradictory reports exist in the literature (especially with regard to bulk blood flow, e.g., Ref. 16), and it remains unclear which specific parameters, if any, may limit oxygen delivery.…”

Impaired Muscle Oxygenation and Elevated Exercise Blood Pressure in Hypertensive Patients

“…50 Postulated mechanisms for these dysfunctions include: (1) the capillary rarefaction and increased perfusion heterogeneity in hypertensives impair flow and oxygen delivery to the working muscles; thus, a greater increase in BP is required to achieve perfusion, and (2) the structural alterations in the resistance vasculature may act as a vascular amplifier that further enhances the effects of a hypertensive stimulus, such as exercise. 12,50 In addition, the impaired oxidative capacity suggestive of mitochondrial dysfunction/uncoupling in the skeletal muscle of hypertensive patients could lead to an increase in reactive oxygen species, reducing endothelial NO synthase, and resulting in a decrease NO bioavailability. 46 The increased oxidative stress and inflammation further reduces NO, promoting endothelial dysfunction within the small vessels' wall and impairing vasodilation in exercising muscles.…”

“…21 In support, animal studies have shown that the reduced microvascular distensibility and rarefaction resulted not only in increased skeletal muscle vascular resistance at resting conditions, but also contributed to a blunted functional hyperemia of skeletal muscles at higher levels of metabolic demand, such as, during exercise. 50 Postulated mechanisms for these dysfunctions include: (1) the capillary rarefaction and increased perfusion heterogeneity in hypertensives impair flow and oxygen delivery to the working muscles; thus, a greater increase in BP is required to achieve perfusion, and (2) the structural alterations in the resistance vasculature may act as a vascular amplifier that further enhances the effects of a hypertensive stimulus, such as exercise. 12,50 In addition, the impaired oxidative capacity suggestive of mitochondrial dysfunction/uncoupling in the skeletal muscle of hypertensive patients could lead to an increase in reactive oxygen species, reducing endothelial NO synthase, and resulting in a decrease NO bioavailability.…”