Oxygen delivery-utilization mismatch in contracting locomotor muscle in COPD: peripheral factors

Medeiros, Wladimir Musetti; Fernandes, Marcelo; Azevedo, Diogo P.; Freitas, Flávia Fernandes Manfredi de; Amorim, Beatriz Oliveira; Chiavegato, Luciana Dias; Hirai, Daniel M.; O’Donnell, Denis E.; Neder, J. Alberto

doi:10.1152/ajpregu.00404.2014

Cited by 21 publications

(34 citation statements)

References 53 publications

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“…However, at maximal KE the patients with COPD demonstrated a marked attenuation in muscle convective O 2 transport (−36%) compared to controls (Figs 2 and 3 and 4), which was the result of both a lower muscle blood flow (−26%) and a lower C aO 2 (−16%) ( Table 2). This is consistent with previous evidence of a reduced convective O 2 delivery during submaximal exercise in patients with COPD (Medeiros et al 2015;Iepsen et al 2017). The lower convective O 2 delivery, in the current patients, was primarily the result of a compromised muscle blood flow, likely resulting from multiple systemic issues related to COPD (e.g.…”

Section: Muscle Convective O 2 Transportsupporting

confidence: 91%

Determinants of the diminished exercise capacity in patients with chronic obstructive pulmonary disease: looking beyond the lungs

Broxterman

Hoff

Wagner

et al. 2020

The Journal of Physiology

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Key pointsr Peak oxygen uptake, a primary determinant of prognosis, mortality and quality of life, is diminished in patients with chronic obstructive pulmonary disease (COPD), with mounting evidence supporting an important role for peripheral dysfunction, particularly within skeletal muscle.r In patients with severe COPD and activity-matched controls, muscle oxygen transport and utilization were assessed at peak effort during single-leg knee-extensor exercise (KE), where ventilation is assumed to be submaximal. This strategy removes ventilation as the major constraint to exercise capacity in COPD, allowing maximal muscle function to be attained and evaluated.r During maximal KE, both convective arterial oxygen delivery to the skeletal muscle microvasculature and subsequent diffusive oxygen delivery to the mitochondria were diminished in patients with COPD compared to control subjects.r These findings emphasize the importance of factors, beyond the lungs, that influence exercise capacity in this patient population and may, ultimately, influence the prognosis, mortality and quality of life for patients with COPD.Abstract Peak oxygen uptake (V O 2 peak ), a primary determinant of prognosis, mortality and quality of life, is diminished in patients with chronic obstructive pulmonary disease (COPD). Mounting evidence supports an important role of the periphery, particularly skeletal muscle, in the diminishedV O 2 peak with COPD. However, the peripheral determinants ofV O 2 peak have not been comprehensively assessed in this cohort. Thus, the hypothesis was tested that both muscle 600 R. M. Broxterman and others J Physiol 598.3convective and diffusive oxygen (O 2 ) transport, and therefore skeletal muscle peak O 2 uptake (V MO 2 peak ), are diminished in patients with COPD compared to matched healthy controls, even when ventilatory limitations (i.e. attainment of maximal ventilation) are minimized by using small muscle mass exercise. Muscle O 2 transport and utilization were assessed at peak exercise from femoral arterial and venous blood samples and leg blood flow (by thermodilution) in eight patients with severe COPD (forced expiratory volume in 1s (FEV 1 ) ± SEM = 0.9 ± 0.1 l, 30% of predicted) and eight controls during single-leg knee-extensor exercise. Both muscle convective O 2 delivery (0.44 ± 0.06 vs. 0.69 ± 0.07 l min −1 , P < 0.05) and muscle diffusive O 2 conductance (6.6 ± 0.8 vs. 10.4 ± 0.9 ml min −1 mmHg −1 , P < 0.05) were ß1/3 lower in patients with COPD than controls, resulting in an attenuatedV MO 2 peak in the patients (0.27 ± 0.04 vs. 0.42 ± 0.05 l min −1 , P < 0.05). When cardiopulmonary limitations to exercise are minimized, the convective and diffusive determinants ofV MO 2 peak , at the level of the skeletal muscle, are greatly attenuated in patients with COPD. These findings emphasize the importance of factors, beyond the lungs, that may ultimately influence this population's prognosis, mortality and quality of life.We are indebted to all of the participants for their time and effort expended to...

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Section: Muscle Convective O 2 Transportsupporting

confidence: 91%

Determinants of the diminished exercise capacity in patients with chronic obstructive pulmonary disease: looking beyond the lungs

Broxterman

Hoff

Wagner

et al. 2020

The Journal of Physiology

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“…This uneven impact of COPD on CI-and CII-driven respiration is further highlighted by the lower CI-to-CII respiration ratio, which gauges the relative capacity of state 3:CI to state 3:CII in patients with COPD compared with control subjects, independent of mitochondrial density ( 2B) (15,31). As discussed previously (15), since CII-driven respiration yields less ATP per oxygen consumed, this reduction in CI/CII respiration may contribute to the increased oxygen cost of exercise reported in patients with COPD (28,41).…”

Section: Discussionmentioning

confidence: 90%

Altered skeletal muscle mitochondrial phenotype in COPD: disease vs. disuse

Gifford

Trinity

Kwon

et al. 2018

Journal of Applied Physiology

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Patients with chronic obstructive pulmonary disease (COPD) exhibit an altered skeletal muscle mitochondrial phenotype, which often includes reduced mitochondrial density, altered respiratory function, and elevated oxidative stress. As this phenotype may be explained by the sedentary lifestyle that commonly accompanies this disease, the aim of this study was to determine whether such alterations are still evident when patients with COPD are compared to control subjects matched for objectively measured physical activity (PA; accelerometry). Indexes of mitochondrial density [citrate synthase (CS) activity], respiratory function (respirometry in permeabilized fibers), and muscle oxidative stress [4-hydroxynonenal (4-HNE) content] were assessed in muscle fibers biopsied from the vastus lateralis of nine patients with COPD and nine PA-matched control subjects (CON). Despite performing similar levels of PA (CON: 18 ± 3, COPD: 20 ± 7 daily minutes moderate-to-vigorous PA; CON: 4,596 ± 683, COPD: 4,219 ± 763 steps per day, P > 0.70), patients with COPD still exhibited several alterations in their mitochondrial phenotype, including attenuated skeletal muscle mitochondrial density (CS activity; CON 70.6 ± 3.8, COPD 52.7 ± 6.5 U/mg, P < 0.05), altered mitochondrial respiration [e.g., ratio of complex I-driven state 3 to complex II-driven state 3 (CI/CII); CON: 1.20 ± 0.11, COPD: 0.90 ± 0.05, P < 0.05), and oxidative stress (4-HNE; CON: 1.35 ± 0.19, COPD: 2.26 ± 0.25 relative to β-actin, P < 0.05). Furthermore, CS activity ( r = 0.55), CI/CII ( r = 0.60), and 4-HNE ( r = 0.49) were all correlated with pulmonary function, assessed as forced expiratory volume in 1 s ( P < 0.05), but not PA ( P > 0.05). In conclusion, the altered mitochondrial phenotype in COPD is present even in the absence of differing levels of PA and appears to be related to the disease itself. NEW & NOTEWORTHY Chronic obstructive pulmonary disease (COPD) is associated with debilitating alterations in the function of skeletal muscle mitochondria. By comparing the mitochondrial phenotype of patients with COPD to that of healthy control subjects who perform the same amount of physical activity each day, this study provides evidence that many aspects of the dysfunctional mitochondrial phenotype observed in COPD are not merely due to reduced physical activity but are likely related to the disease itself.

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“…31), and therefore better reflects the deoxygenation status of the muscle under the probe; and 2) changes in HHb are assumed to be localized within the capillary-venous compartment, at least under conditions where change in arterial saturation or Hb concentration is unlikely. Thus, by conceptually replacing venous oxygen concentration in the Fick equation, NIRS-derived ⌬HHb measurement is commonly used as a noninvasive surrogate for microvascular O 2 extraction (e.g., 6,8,9,13,17,28,34). However, ⌬HHb depends on 1) extraction-related mechanisms, or Q /V O 2 ; and 2) microvascular hematocrit and/or tissue blood-vessel-volumerelated mechanisms that influence heme concentration within the interrogated tissue.…”

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confidence: 99%

Changes in whole tissue heme concentration dissociates muscle deoxygenation from muscle oxygen extraction during passive head-up tilt

Adami

Koga

Kondo

et al. 2015

Journal of Applied Physiology

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Skeletal muscle deoxygenated hemoglobin and myoglobin concentration ([HHb]), assessed by near-infrared spectroscopy (NIRS), is commonly used as a surrogate of regional O2 extraction (reflecting the O2 delivery-to-consumption ratio, Q̇/V̇o2). However, [HHb] change (Δ[HHb]) is also influenced by capillary-venous heme concentration, and/or small blood vessel volume (reflected in total heme; [THb]). We tested the hypotheses that Δ[HHb] is associated with O2 extraction, and insensitive to [THb], over a wide range of Q̇/V̇o2 elicited by passive head-up tilt (HUT; 10-min, 15° increments, between -10° and 75°). Steady-state common femoral artery blood flow (FBF) was measured by echo-Doppler, and time-resolved NIRS measured [HHb] and [THb] of vastus lateralis (VL) and gastrocnemius (GS) in 13 men. EMG confirmed muscles were inactive. During HUT in VL [HHb] increased linearly (57 ± 10 to 101 ± 16 μM; P < 0.05 above 15°) and was associated (r(2) ∼ 0.80) with the reduction in FBF (618 ± 75 ml/min at 0° to 268 ± 52 ml/min at 75°; P < 0.05 above 30°) and the increase in [THb] (228 ± 30 vs. 252 ± 32 μM; P < 0.05 above 15°). GS response was qualitatively similar to VL. However, there was wide variation within and among individuals, such that the overall limits of agreement between Δ[HHb] and ΔFBF ranged from -35 to +19% across both muscles. Neither knowledge of tissue O2 saturation nor vascular compliance could appropriately account for the Δ[HHb]-ΔFBF dissociation. Thus, under passive tilt, [HHb] is influenced by Q̇/V̇o2, as well as microvascular hematocrit and/or tissue blood vessel volume, complicating its use as a noninvasive surrogate for muscle microvascular O2 extraction.

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Oxygen delivery-utilization mismatch in contracting locomotor muscle in COPD: peripheral factors

Cited by 21 publications

References 53 publications

Determinants of the diminished exercise capacity in patients with chronic obstructive pulmonary disease: looking beyond the lungs

Determinants of the diminished exercise capacity in patients with chronic obstructive pulmonary disease: looking beyond the lungs

Altered skeletal muscle mitochondrial phenotype in COPD: disease vs. disuse

Changes in whole tissue heme concentration dissociates muscle deoxygenation from muscle oxygen extraction during passive head-up tilt

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