Skeletal Muscle Perfusion Research Articles

Improvement of the microcirculation in the acute ischemic rat limb during intravenous infusion of drag-reducing polymers

Drag-reducing polymers (DRPs) are blood-soluble macromolecules that can increase blood flow and reduce vascular resistance. The purpose of the present study is to examine the effects of DRPs on microcirculation in rat hind limb during acute femoral artery occlusion. Two groups of 20 male Wistar rats were subjected to either hemodynamic measurement or contrast enhanced ultrasound (CEU) imaging during peripheral ischemia. Both groups were further subdivided into a DRP-treated group or a saline-treated group. Polyethylene oxide (PEO) was chosen as the test DRP, and rats were injected with either 10 ppm PEO solution or saline through the caudal vein at a constant rate of 5 ml/h for 20 min. Abdominal aortic flow, iliac artery pressure, iliac vein pressure, heart rate, carotid artery pressure and central venous pressure (CVP) were monitored, and vascular resistance was calculated by (iliac artery pressure-iliac vein pressure)/abdominal aortic blood flow. Flow perfusion and capillary volume of skeletal muscle were measured by CEU. During PEO infusion, abdominal aortic blood flow increased (p<0.001) and vascular resistance decreased (p<0.001) compared to rats that received saline during peripheral ischemia. There was no significant change in ischemic skeletal capillary volume (A) with DRP treatment (p>0.05), but red blood cell velocity (β) and capillary blood flow (A×β) increased significantly (p<0.05) during PEO infusion. In addition, A, β and A×β all increased (p<0.05) in the contralateral hind limb muscle. In contrast, PEO had no significant influence on heart rate, mean carotid artery blood pressure or CVP. Intravenous infusion of drag reducing polymers may offer a novel hydrodynamic approach for improving microcirculation during acute peripheral ischemia.

Mutant hypoxia inducible factor-1α improves angiogenesis and tissue perfusion in ischemic rabbit skeletal muscle

Hypoxia-inducible factor-1α (HIF-1α) is one of the most potent angiogenic growth factors. It regulates genes involved in angiogenesis, but is inactivated rapidly by normoxia. Ad-HIF-1α-Trip was constructed by transforming Pro402, Pro564, and Asn803 in HIF-1α to alanine in order to delay degradation and create a constitutive transcriptional activator. In this study, we investigated whether Ad-HIF-1α-Trip could induce functional mature angiogenesis and the possible mechanisms involved. We found that Ad-HIF-1α-Trip increased the expression of multiple angiogenic genes in cultured HMVEC-Ls, including VEGF, PLGF, PAI-1, and PDGF. In a rabbit model of acute hind limb ischemia, Ad-HIF-1α-Trip improved tissue perfusion and collateral vessels, as measured by contrast-enhanced ultrasound (CEU), CT angiography, and vascular casting. Ad-HIF-1α-Trip also produced more histologically identifiable capillaries, which were verified by immunostaining, compared with controls. Interestingly, inhibition of CBP/p300 by curcumin prevented HIF-1α from inducing the expression of several angiogenic genes. The present study suggests that Ad-HIF-1α-Trip can induce mature angiogenesis and improve tissue perfusion in ischemic rabbit skeletal muscle. CBP/p300, which interacts with the transactivation domains of HIF-1α, is important for HIF-1α-induced transcription of angiogenic genes.

Image‐based calculation of perfusion and oxyhemoglobin saturation in skeletal muscle during submaximal isometric contractions

The relative oxygen saturation of hemoglobin and the rate of perfusion are important physiological quantities, particularly in organs such as skeletal muscle, in which oxygen delivery and use are tightly coupled. The purpose of this study was to demonstrate the image-based calculation of the relative oxygen saturation of hemoglobin and quantification of perfusion in skeletal muscle during isometric contractions. This was accomplished by establishing an empirical relationship between the rate of radiofrequency-reversible dephasing and near-infrared spectroscopy-observed oxyhemoglobin saturation (relative oxygen saturation of hemoglobin) under conditions of arterial occlusion and constant blood volume. A calibration curve was generated and used to calculate the relative oxygen saturation of hemoglobin from radiofrequency-reversible dephasing changes measured during contraction. Twelve young healthy subjects underwent 300 s of arterial occlusion and performed isometric contractions of the dorsiflexors at 30% of maximal contraction for 120 s. Muscle perfusion was quantified during contraction by arterial spin labeling and measures of muscle T(1). Comparisons between the relative oxygen saturation of hemoglobin values predicted from radiofrequency-reversible dephasing and that measured by near-infrared spectroscopy revealed no differences between methods (P = 0.760). Muscle perfusion reached a value of 34.7 mL 100 g(-1) min(-1) during contraction. These measurements hold future promise in measuring muscle oxygen consumption in healthy and diseased skeletal muscle.

Loss of insulin‐mediated microvascular perfusion in skeletal muscle is associated with the development of insulin resistance

The aetiology of the development of type 2 diabetes remains unresolved. In the present study, we assessed whether an impairment of insulin-mediated microvascular perfusion occurs early in the onset of insulin resistance. Hooded Wistar rats were fed either a normal diet (ND) or a high-fat diet (HFD) for 4 weeks. Anaesthetized animals were subjected to an isoglycaemic hyperinsulinaemic clamp (3 or 10 mU/min/kg x 2 h), and measurements were made of glucose infusion rate (GIR), hindleg glucose uptake, muscle glucose uptake by 2-deoxy-d-glucose (R'g), glucose appearance (Ra), glucose disappearance (Rd), femoral blood flow (FBF) and hindleg 1-methylxanthine disappearance (1-MXD, an index of microvascular perfusion). Compared with ND-fed animal, HFD feeding led to a mild increase in fasting plasma glucose and plasma insulin, without an increase in total body weight. During the clamps, HFD rats showed an impairment of insulin-mediated action on GIR, hindleg glucose uptake, R'g, Ra, Rd and FBF, with a greater loss of insulin responsiveness at 3 mU/min/kg than at 10 mU/min/kg. The HFD also impaired insulin-mediated microvascular perfusion as assessed by 1-MXD. Interestingly, 1-MXD was the only measurement that remained unresponsive to the higher dose of 10 mU/min/kg insulin. We conclude that the early stage of insulin resistance is characterized by an impairment of the insulin-mediated microvascular responses in skeletal muscle. This is likely to cause greater whole body insulin resistance by limiting the delivery of hormones and nutrients to muscle.

Perfusion heterogeneity does not explain excess muscle oxygen uptake during variable intensity exercise

The association between muscle oxygen uptake (VO(2)) and perfusion or perfusion heterogeneity (relative dispersion, RD) was studied in eight healthy male subjects during intermittent isometric (1 s on, 2 s off) one-legged knee-extension exercise at variable intensities using positron emission tomography and a-v blood sampling. Resistance during the first 6 min of exercise was 50% of maximal isometric voluntary contraction force (MVC) (HI-1), followed by 6 min at 10% MVC (LOW) and finishing with 6 min at 50% MVC (HI-2). Muscle perfusion and O(2) delivery during HI-1 (26 +/- 5 and 5.4 +/- 1.0 ml 100 g(-1) min(-1)) and HI-2 (28 +/- 4 and 5.8 +/- 0.7 ml 100 g(-1) min(-1)) were similar, but both were higher (P<0.01) than during LOW (15 +/- 3 and 3.0 +/- 0.6 ml 100 g(-1) min(-1)). Muscle VO(2) was also higher during both HI workloads (HI-1 3.3 +/- 0.4 and HI-2 4.1 +/- 0.6 ml 100 g(-1) min(-1)) than LOW (1.4 +/- 0.4 ml 100 g(-1) min(-1); P<0.01) and 25% higher during HI-2 than HI-1 (P<0.05). O(2) extraction was higher during HI workloads (HI-1 62 +/- 7 and HI-2 70 +/- 7%) than LOW (45 +/- 8%; P<0.01). O(2) extraction tended to be higher (P = 0.08) during HI-2 when compared to HI-1. Perfusion was less heterogeneous (P<0.05) during HI workloads when compared to LOW with no difference between HI workloads. Thus, during one-legged knee-extension exercise at variable intensities, skeletal muscle perfusion and O(2) delivery are unchanged between high-intensity workloads, whereas muscle VO(2) is increased during the second high-intensity workload. Perfusion heterogeneity cannot explain this discrepancy between O(2) delivery and uptake. We propose that the excess muscle VO(2) during the second high-intensity workload is derived from working muscle cells.

Regulation of human skeletal muscle perfusion and its heterogeneity during exercise in moderate hypoxia

Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to approximately 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion of aminophylline. Systemic hypoxia reduced oxygen extraction of the limb but increased muscle BF, and this flow increment was confined solely to the exercising quadriceps femoris muscle. Exercising muscle BF heterogeneity was reduced from rest (P = 0.055) but was not affected by hypoxia. Adenosine receptor inhibition had no effect on capillary BF during exercise in either normoxia or hypoxia. Finally, one-leg exercise increased muscle BF heterogeneity both in the resting posterior hamstring part of the exercising leg and in the resting contralateral leg, whereas mean BF was unchanged. In conclusion, the results show that increased BF during one-leg exercise in moderate hypoxia is confined only to the contracting muscles, and the working muscle hyperemia appears not to be directly mediated by adenosine. Increased flow heterogeneity in noncontracting muscles likely reflects sympathetic nervous constraints to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise.

Altered Spatio‐Temporal Microvascular Blood Flow Distribution Patterns in Skeletal Muscle with Metabolic Syndrome

A characteristic of peripheral vascular disease (PVD) in the metabolic syndrome (MS) is impaired skeletal muscle perfusion:demand matching, with increased adrenergic tone being a contributing element. However, despite increases in bulk perfusion to contracting muscle following adrenoreceptor blockade, fatigue resistance remains poor unless endothelial function is restored by treatment with antioxidants. Given that antioxidant treatment alone improves neither active hyperemia nor muscle fatigue, these observations suggest that additional processes are involved beyond simple bulk perfusion. Using in situ cremaster muscle, we determined that spatial perfusion heterogeneity at bifurcations was elevated in obese Zucker rats (OZR) vs. control and this pattern was repeated at multiple successive bifurcations in the network. The increased spatial heterogeneity was not compensated for via temporal activity, as perfusion distribution at bifurcations was less labile in OZR vs. control. Intravascular tracer washout (albumin) revealed an increased heterogeneity at the network level of resolution, correctable following adrenoreceptor blockade. These observations suggest that a critical component of PVD in MS is a shift in the spatio‐temporal distribution of perfusion at bifurcations in skeletal muscle and that only interventions that improve this will have a beneficial impact on tissue performance.

Comparison of exogenous adenosine and voluntary exercise on human skeletal muscle perfusion and perfusion heterogeneity

Adenosine is a widely used pharmacological agent to induce a "high-flow" control condition to study the mechanisms of exercise hyperemia, but it is not known how well an adenosine infusion depicts exercise-induced hyperemia, especially in terms of blood flow distribution at the capillary level in human muscle. Additionally, it remains to be determined what proportion of the adenosine-induced flow elevation is specifically directed to muscle only. In the present study, we measured thigh muscle capillary nutritive blood flow in nine healthy young men using PET at rest and during the femoral artery infusion of adenosine (1 mg min(-1) l thigh volume(-1)), which has previously been shown to induce a maximal whole thigh blood flow of approximately 8 l/min. This response was compared with the blood flow induced by moderate- to high-intensity one-leg dynamic knee extension exercise. Adenosine increased muscle blood flow on average to 40 +/- 7 ml x min(-1) x 100 g muscle(-1) with an aggregate value of 2.3 +/- 0.6 l/min for the whole thigh musculature. Adenosine also induced a substantial change in blood flow distribution within individuals. Muscle blood flow during the adenosine infusion was comparable with blood flow in moderate- to high-intensity exercise (36 +/- 9 ml x min(-1) x 100 g muscle(-1)), but flow heterogeneity was significantly higher during the adenosine infusion than during voluntary exercise. In conclusion, a substantial part of the flow increase in the whole limb blood flow induced by a high-dose adenosine infusion is conducted through the physiological non-nutritive shunt in muscle and/or also through tissues of the limb other than muscle. Additionally, an intra-arterial adenosine infusion does not mimic exercise hyperemia, especially in terms of muscle capillary flow heterogeneity, while the often-observed exercise-induced changes in capillary blood flow heterogeneity likely reflect true changes in nutritive flow linked to muscle fiber and vascular unit recruitment.

Antioxidants and aging: NMR-based evidence of improved skeletal muscle perfusion and energetics

We sought to examine the potential role of oxidative stress on skeletal muscle function with advancing age. Nuclear magnetic resonance (NMR) was employed to simultaneously assess muscle perfusion (arterial spin labeling) and energetics ((31)P NMR spectroscopy) in the lower leg of young (26 + or - 5 yr, n = 6) and older (70 + or - 5 yr, n = 6) healthy volunteers following the consumption of either placebo (PL) or an oral antioxidant (AO) cocktail (vitamins C and E and alpha-lipoic acid), previously documented to decrease plasma free radical concentration. NMR measurements were made during and after 5 min of moderate intensity (approximately 5 W) plantar flexion exercise. AO administration significantly improved end-exercise perfusion (AO, 50 + or - 5, and PL, 43 + or - 4 ml x 100 g(-1) x min(-1)) and postexercise perfusion area under the curve (AO, 1,286 + or - 236, and PL, 866 + or - 144 ml/100 g) in older subjects, whereas AO administration did not alter hemodynamics in the young group. Concomitantly, muscle oxidative capacity (time constant of phosphocreatine recovery, tau) was improved following AO in the older (AO, 43 + or - 1, and PL, 51 + or - 7 s) but not the young (AO, 54 + or - 5, and PL, 48 + or - 7 s) group. These findings support the concept that oxidative stress may be partially responsible for the age-related decline in skeletal muscle perfusion during physical activity and reveal a muscle metabolic reserve capacity in the elderly that is accessible under conditions of improved perfusion.

Real-Time Contrast-Enhanced Ultrasound for the Assessment of Perfusion Dynamics in Skeletal Muscle

We developed a real-time low-MI contrast-enhanced ultrasound method (CEUS), compared it with venous occlusion plethysmography (VOP) and evaluated its robustness in the quantification of skeletal muscle perfusion during exercise. Contrast pulse sequencing (7 MHz) during continuous intravenous infusion of SonoVue (4.8 mL/300s) was used repeatedly in eight healthy volunteers to monitor changes of the muscle perfusion before, during and after isometric exercises (10 to 50% of individual maximum strength for 20 to 30 s) of the gastrocnemius muscle in real time. CEUS was correlated with VOP at different time points, and the exactness of several CEUS parameters obtained from ultrasound-signal-intensity-time curves was evaluated. Real-time CEUS depicted a large variability of the skeletal muscle blood volume at rest (mean, 3.48; range, 0.60 to 9.92 [∼mL]), with a significant reproducibility (r = 0.72, p < 0.05) and correlation with VOP (r = 0.59, p < 0.001). Mean blood volume during exercise was 1.58(∼mL), increased to a mean maximum after exercise of 8.88(∼mL), the mean change of the local blood volume during and directly after the exercise was –0.10 and +1.57(∼mL/s). The average CEUS signal during exercise decreased (mean area under the curve, –50.4[∼mL·s]) and subsequently increased post exercise (mean 118.6[∼mL·s]). CEUS parameters could be calculated with mean relative errors between 6 and 36%. Continuous assessment of local muscle microcirculation during exercise is possible with real-time CEUS with an acceptable robustness. Its application may be of particular interest in a better understanding of the role of perfusion during muscle training, and the monitoring of pathological vascular response, such as in diabetic microvessel diseases. (E-mail: martin.krix@kabelbw.de)

Exercise-induced reduction in systemic vascular resistance: A covert killer and an unrecognised resuscitation challenge?

Systemic vascular resistance falls in exercise as a consequence of metabolically-linked vasodilatation in active skeletal muscles. This exercise-induced vasodilatation is closely linked with reduced muscle tissue oxygen tension in and is characterised by reduced response to adrenergic vasoconstrictor mechanisms which is often referred to as functional sympatholysis. Systemic arterial blood pressure in exercise is maintained at normal or, more commonly, at elevated levels by increase in cardiac output and increased sympathetic vasomotor tone. Recovery of normal resting skeletal muscle tissue oxygen tension and skeletal muscle vascular tone after exercise depends on the post-exercise recovery process. This process requires ongoing elevated skeletal muscle perfusion and can therefore be predicted to be impaired in shock and cardiopulmonary resuscitation scenarios. Comprehensive consideration of this exercise physiology and its extrapolation into shock, cardiac arrest and resuscitation scenarios supports the proposal that exercise-induced sympatholytic vasodilatation in skeletal muscle may be of considerable unrecognised significance for resuscitation medicine. MAIN HYPOTHESIS: Reduced systemic vascular resistance due to pre-existing exercise-induced sympatholytic vasodilatation in skeletal muscle can significantly exacerbate systemic arterial hypotension in acute shock states and resuscitation scenarios. SUB-HYPOTHESES: 1. Onset of syncope, clinical shock states and pulseless electrical activity can occur at significantly higher cardiac output levels in subjects who were engaged in immediate pre-morbid exercise as compared to resting subjects. 2. The efficacy of external chest compression in generating coronary and cerebral perfusion in cardiopulmonary resuscitation can be significantly impaired when cardiac arrest has occurred during exercise. 3. The efficacy of adrenergic vasopressor agents in resuscitation scenarios can be significantly impaired in subjects who were engaged in immediate pre-morbid exercise. The limited available evidence is compatible with the hypothesis being true but does not provide direct confirmation. There is no evidence available directly supporting or refuting the hypothesis. Significant potential clinical implications are outlined relating to the management of cardiopulmonary and trauma resuscitation for patients who were involved in immediate pre-morbid exercise, particularly, but not exclusively, at higher exercise intensities. There are also significant potential prognostic implications. Reduction in systemic vascular resistance due to exercise-induced sympatholytic vasodilatation in skeletal muscle may largely explain the reported poor success rate for cardiopulmonary resuscitation with prompt defibrillation for sudden cardiac arrest in young previously healthy athletes. Investigation of this unexplored area of pathophysiology poses major difficulties but could lead to significant improvements in the outcomes of resuscitation for patients who were involved in immediate pre-morbid exercise.

Vasomotion and insulin‐mediated capillary recruitment – part of the explanation?

Vasomotion and insulin‐mediated capillary recruitment – part of the explanation?

A large slice of cardiac output or humble pie for the respiratory muscles?

A large slice of cardiac output or humble pie for the respiratory muscles?

NMR-based Evidence Of Improved Skeletal Muscle Perfusion And Energetics In The Elderly Following Acute Antioxidant Administration

NMR-based Evidence Of Improved Skeletal Muscle Perfusion And Energetics In The Elderly Following Acute Antioxidant Administration

Multiparametric NMR-Based Assessment of Skeletal Muscle Perfusion and Metabolism During Exercise in Elderly Persons: Preliminary Findings

Aging is associated with a decline in exercise capacity that may be attributable to maladaptations in both skeletal muscle perfusion and metabolism; yet very little is known regarding the real-time, within-muscle interplay between these parameters during physical activity. Therefore, we utilized an unique nuclear magnetic resonance sequence to concomitantly examine changes in lower leg skeletal muscle perfusion and metabolism. In young (26+/-5 years, n=6) and older (70+/-5 years, n=6) healthy volunteers, arterial spin labeling measurements of muscle perfusion were combined with 31 Phosphorous (31P) nuclear magnetic resonance spectroscopy to monitor high-energy phosphate metabolites during and after 5 minutes of moderate-intensity (approximately 5W) plantar flexion exercise. Compared with young, end-exercise perfusion was diminished in older participants (43+/-10 mL/100 g/minute, old; 60+/-7 mL/100 g.minute, young), accompanied by greater phosphocreatine (PCr) depletion (-28%+/-12%, old; -19%+/-7%, young) and elevated inorganic phosphate/PCr (0.41+/-0.2, old; 0.24+/-0.09, young); yet the time constant for PCr recovery (tau, an index of muscle oxidative capacity) was similar between groups (51+/-17 seconds, old; 48+/-7 seconds, young). Together, these preliminary data provide evidence of an age-related decline in tissue perfusion and increased "metabolic stress" during exercise but demonstrate that overall oxidative capacity in the elderly does not appear negatively affected by this relatively hypoperfused state.

M.3243A&amp;gt;G Mutation in Mitochondrial DNA Leads to Decreased Insulin Sensitivity in Skeletal Muscle and to Progressive β-Cell Dysfunction

OBJECTIVE—To study insulin sensitivity and perfusion in skeletal muscle together with the β-cell function in subjects with the m.3243A>G mutation in mitochondrial DNA, the most common cause of mitochondrial diabetes.RESEARCH DESIGN AND METHODS—We measured skeletal muscle glucose uptake and perfusion using positron emission tomography and 2-[18F]fluoro-2-deoxyglucose and [15O]H2O during euglycemic hyperinsulinemia in 15 patients with m.3243A>G. These patients included five subjects with no diabetes as defined by the oral glucose tolerance test (OGTT) (group 1), three with GHb <6.1% and newly found diabetes by OGTT (group 2), and seven with a previously diagnosed diabetes (group 3). Control subjects consisted of 13 healthy individuals who were similar to the carriers of m.3243A>G with respect to age and physical activity. β-Cell function was assessed using the OGTT and subsequent mathematical modeling.RESULTS—Skeletal muscle glucose uptake was significantly lower in groups 1, 2, and 3 than in the control subjects. The glucose sensitivity of β-cells in group 1 patients was similar to that of the control subjects, whereas in group 2 and 3 patients, the glucose sensitivity was significantly lower. The insulin secretion parameters correlated strongly with the proportion of m.3243A>G mutation in muscle.CONCLUSIONS—Our findings show that subjects with m.3243A>G are insulin resistant in skeletal muscle even when β-cell function is not markedly impaired or glucose control compromised. We suggest that both the skeletal muscle insulin sensitivity and the β-cell function are affected before the onset of the mitochondrial diabetes caused by the m.3243A>G mutation.

Therapeutic angiogenesis with placental growth factor improves exercise tolerance of ischaemic rabbit hindlimbs

We investigated the effects of angiogenic gene therapy with adenoviral placental growth factor(131) (AdPlGF) on aerobic capacity and exercise tolerance in a rabbit hindlimb ischaemia model. We also assessed whether strong angiogenic changes such as capillary arterialization and formation of artery-venous shunts compromise oxygen transport to target tissues resulting in suboptimal therapeutic efficacy. Hindlimb ischaemia was surgically induced in New Zealand White rabbits (n = 20) that a day later received intramuscular (i.m.) AdPlGF or AdLacZ (3 x 10(11)vp) gene transfer (GT). Corresponding GTs were also done in healthy non-ischaemic rabbits (n = 10). Muscle energy metabolism and skeletal muscle perfusion were studied non-invasively before GT and at 6 and 28 days using (31)P-magnetic resonance spectroscopy and contrast pulse sequence ultrasound, respectively. Oedema was quantified using modified Miles assay at sacrifice. AdPlGF increased perfusion 7.8-fold and improved aerobic capacity of ischaemic limbs 45% compared with AdLacZ controls (P < 0.05) at 6 days. In non-ischaemic limbs, strong angiogenic response to GT, including capillary arterialization and acute oedema, did not impair muscle energy metabolism. This study shows that proangiogenic gene therapy can significantly improve performance of ischaemic limbs and supports the concept of therapeutic angiogenesis for the treatment of patients with ischaemia.

Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle

Insulin has an exercise-like action to increase microvascular perfusion of skeletal muscle and thereby enhance delivery of hormone and nutrient to the myocytes. With insulin resistance, insulin's action to increase microvascular perfusion is markedly impaired. This review examines the present status of these observations and techniques available to measure such changes as well as the possible underpinning mechanisms. Low physiological doses of insulin and light exercise have been shown to increase microvascular perfusion without increasing bulk blood flow. In these circumstances, blood flow is proposed to be redirected from the nonnutritive route to the nutritive route with flow becoming dominant in the nonnutritive route when insulin resistance has developed. Increased vasomotion controlled by vascular smooth muscle may be part of the explanation by which insulin mediates an increase in microvascular perfusion, as seen from the effects of insulin on both muscle and skin microvascular blood flow. In addition, vascular dysfunction appears to be an early development in the onset of insulin resistance, with the consequence that impaired glucose delivery, more so than insulin delivery, accounts for the diminished glucose uptake by insulin-resistant muscle. Regular exercise may prevent and ameliorate insulin resistance by increasing "vascular fitness" and thereby recovering insulin-mediated capillary recruitment.

Quantitative, dynamic and noninvasive determination of skeletal muscle perfusion in mouse leg by NMR arterial spin-labeled imaging

Because mouse may relatively easily be genetically tailored to develop equivalent of human muscular diseases or to present controlled alterations of mechanisms involved in vasoregulation, it has become the prevalent species to explore such questions. However, the very small size of the animals represents a serious limitation when evaluating the functional consequences of these genetic manipulations. In this context, the recourse to arterial spin labeling (ASL) nuclear magnetic resonance (NMR) methods in which arterial water spins act as an endogenous and freely diffusible tracer of perfusion is tempting but challenging. This article shows that despite the small size of the animal, mouse muscle perfusion may be measured, at rest and in conditions of reactive hyperemia, using saturation inversion recovery sequence, a pulsed ASL variant, combined with NMR imaging. Baseline perfusion values in the mouse leg were 17+/-11 ml.min(-1).100 g(-1) (n=11) and were comparable to microsphere data from the literature. Under ischemia, leg perfusion was 1.2+/-9.3 ml.min(-1).100 g(-1) (n=11). The difference observed between basal and ischemic measurements was statistically different (P=.0001). The temporal pattern of hyperemia in mouse muscle was coherent with previously published measurements in humans and in rats. The mean peak perfusion was 62+/-24 ml.min(-1).100 g(-1) (n=6) occurring 48+/-27 s after the end of occlusion. In conclusion, this study demonstrated the ability of ASL combined to NMR imaging to quantify skeletal muscle perfusion in mice legs, both at rest and dynamically.

Restrictions in systemic and locomotor skeletal muscle perfusion, oxygen supply andVO2during high‐intensity whole‐body exercise in humans

Perfusion to exercising skeletal muscle is regulated to match O(2) delivery to the O(2) demand, but this regulation might be compromised during or approaching maximal whole-body exercise as muscle blood flow for a given work rate is blunted. Whether muscle perfusion is restricted when there is an extreme metabolic stimulus to vasodilate during supramaximal exercise remains unknown. To examine the regulatory limits of systemic and muscle perfusion in exercising humans, we measured systemic and leg haemodynamics, O(2) transport, and , and estimated non-locomotor tissue perfusion during constant load supramaximal cycling (498 +/- 16 W; 110% of peak power; mean +/- S.E.M.) in addition to both incremental cycling and knee-extensor exercise to exhaustion in 13 trained males. During supramaximal cycling, cardiac output (Q), leg blood flow (LBF), and systemic and leg O(2) delivery and reached peak values after 60-90 s and thereafter levelled off at values similar to or approximately 6% (P < 0.05) below maximal cycling, while upper body blood flow remained unchanged (approximately 5.5 l min(-1)). In contrast, Q and LBF increased linearly until exhaustion during one-legged knee-extensor exercise accompanying increases in non-locomotor tissue blood flow to approximately 12 l min(-1). At exhaustion during cycling compared to knee-extensor exercise, Q, LBF, leg vascular conductance, leg O(2) delivery and leg for a given power were reduced by 32-47% (P < 0.05). In conclusion, locomotor skeletal muscle perfusion is restricted during maximal and supramaximal whole-body exercise in association with a plateau in Q and limb vascular conductance. These observations suggest that limits of cardiac function and muscle vasoconstriction underlie the inability of the circulatory system to meet the increasing metabolic demand of skeletal muscles and other tissues during whole-body exercise.