Each-step activation of oxidative phosphorylation is necessary to explain muscle metabolic kinetic responses to exercise and recovery in humans

To better understand muscle bioenergetic regulation, a previously-developed model of the skeletal muscle cell bioenergetic system was used to simulate the influence of: 1) each step activation (ESA) of NADH supply (including glycolysis) and oxidative phosphorylation (OXPHOS) complexes; and 2) glycolytic inhibition by protons, on the kinetics of ATP synthesis from OXPHOS, anaerobic glycolysis and creatine kinase (CK). Simulations were fitted to previously published experimental data of ATP production fluxes and metabolite concentrations during moderate and severe intensity exercise transitions in bilateral knee-extension in humans. Overall, computer simulations agreed well with experimental results. Specifically, a large (>5-fold) direct activation of all OXPHOS complexes was required to simulate measured phosphocreatine (PCr) and OXPHOS responses to both moderate and severe intensity exercise. In addition, slow decay of ESA was required to fit PCr recovery kinetics, and the time constant of ESA decay was slower following severe (180s) than moderate (90s) exercise. Additionally, a strong inhibition of (anaerobic) glycolysis by protons (glycolytic rate inversely proportional to the cube of proton concentration) provided the best fit to the experimental pH kinetics, and may contribute to the progressive increase in oxidative ATP supply during acidifying contractions. During severe-intensity exercise an ‘additional’ ATP usage (a 27% increase at 8 min, above the initial ATP supply) was necessary to explain the observed V̇O2 slow component. Thus parallel activation of ATP usage and ATP supply (ESA), and a strong inhibition of ATP supply by anaerobic glycolysis, were necessary to simulate the kinetics of muscle bioenergetics observed in humans

Last Word on Viewpoint: Principles, insights, and potential pitfalls of the noninvasive determination of muscle oxidative capacity by near-infrared spectroscopy

Skeletal muscle oxidative capacity is highly plastic, strongly associated with whole-body aerobic capacity (16, 18) and state of health. Loss of muscle oxidative capacity is associated with physical inactivity, aging and chronic disease (17), and has been implicated in the pathophysiology of obesity and diabetes (21). Evaluating these changes has traditionally been limited to invasive or costly assessments (biopsy or ³¹P MRS). To address this, Hamaoka and colleagues developed an innovative, non-invasive approach using near-infrared spectroscopy (NIRS) to quantitatively measure muscle oxygen consumption (mV̇O₂; 12) and use this to infer muscle oxidative capacity based on the mV̇O₂ recovery rate constant (k) (23; later modified 26). This technique has been subsequently used to interpret relative differences in oxidative capacity across a wide range of muscles, ages and disease states (Figure 1C). The purpose of this Viewpoint is to open a discussion on the principles, insights and potential pitfalls of using NIRS to measure k and infer muscle oxidative capacity

Reproducibility of NIRS Assessment of Muscle Oxidative Capacity in Smokers With and Without COPD

Low muscle oxidative capacity contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). Near-infrared spectroscopy (NIRS) allows non-invasive determination of the muscle oxygen consumption (mV̇O2) recovery rate constant (k), which is proportional to oxidative capacity assuming two conditions are met: 1) exercise intensity is sufficient to fully-activate mitochondrial oxidative enzymes; 2) sufficient O2 availability. We aimed to determine reproducibility (coefficient of variation, CV; intraclass correlation coefficient, ICC) of NIRS k assessment in the gastrocnemius of 64 participants with (FEV1 64 ± 23%predicted) or without COPD (FEV1 98 ± 14%predicted). 10–15 s dynamic contractions preceded 6 min of intermittent arterial occlusions (5–10 s each, ∼250 mmHg) for k measurement. k was lower (P < 0.05) in COPD (1.43 ± 0.4 min−1; CV = 9.8 ± 5.9%, ICC = 0.88) than controls (1.74 ± 0.69 min−1; CV = 9.9 ± 8.4%; ICC = 0.93). Poor k reproducibility was more common when post-contraction mV̇O2 and deoxygenation were low, suggesting insufficient exercise intensity for mitochondrial activation and/or the NIRS signal contained little light reflected from active muscle. The NIRS assessment was well tolerated and reproducible for muscle dysfunction evaluation in COPD

Exercise, Ageing and The Lung

This review provides a pulmonary-focused description of the age-associated changes in the integrative physiology of exercise, including how declining lung function plays a role in promoting multimorbidity in the elderly through limitation of physical function. We outline the ageing of physiologic systems supporting endurance activity: 1) coupling of muscle metabolism to mechanical power output; 2) gas transport between muscle capillary and mitochondria; 3) matching of muscle blood flow to its requirement; 4) oxygen and carbon dioxide carrying capacity of the blood; 5) cardiac output; 6) pulmonary vascular function; 7) pulmonary oxygen transport; 8) control of ventilation; 9) pulmonary mechanics and respiratory muscle function. Deterioration in function occurs in many of these systems in healthy ageing. Between the ages of 25 and 80 pulmonary function and aerobic capacity each decline by ~40%. While the predominant factor limiting exercise in the elderly likely resides within the function of the muscles of ambulation, muscle function is (at least partially) rescued by exercise training. The age associated decline in pulmonary function, however, is not recovered by training. Thus, loss in pulmonary function may lead to ventilatory limitation in exercise in active elderly, limiting the ability to accrue the health benefits of physical activity into senescence

Unaltered V̇O2 kinetics despite greater muscle oxygenation during heavy-intensity two-legged knee extension versus cycle exercise in humans

Relative perfusion of active muscles is greater during knee extension ergometry (KE) than cycle ergometry (CE). This provides the opportunity to investigate the effects of increased O₂ delivery (Q̇O₂) on deoxygenation heterogeneity among quadriceps muscles and pulmonary V̇O₂ kinetics. Using time-resolved near-infrared spectroscopy, we hypothesized that compared with CE the superficial vastus lateralis (VL), superficial rectus femoris and deep VL in KE would have 1) a smaller amplitude of the exercise-induced increase in deoxy[Hb+Mb] (related to the balance between V̇O₂ and Q̇O₂); 2) a greater amplitude of total[Hb+Mb] (related to the diffusive O₂ conductance); 3) a greater homogeneity of regional muscle deoxy[Hb+Mb]; and 4) no difference in pulmonary V̇O₂ kinetics. Eight participants performed square-wave KE and CE exercise from 20 W to heavy work rates. Deoxy[Hb+Mb] amplitude was less for all muscle regions in KE (P<0.05: superficial, KE 17-24 vs. CE 19-40; deep, KE 19 vs. CE 26 μM). Further, the amplitude of total[Hb+Mb] was greater for KE than CE at all muscle sites (P<0.05: superficial, KE 7-21 vs. CE 1-16; deep, KE 11 vs. CE -3 μM). Although the amplitude and heterogeneity of deoxy[Hb+Mb] was significantly lower in KE than CE during the first minute of exercise, the pulmonary V̇O₂ kinetics was not different for KE and CE. These data show that the microvascular Q̇O₂ to V̇O₂ ratio, and thus tissue oxygenation, was greater in KE than CE. This suggests that pulmonary and muscle V̇O₂ kinetics in young healthy humans are not limited by Q̇O₂ during heavy-intensity cycling

Reliability and Physiological Interpretation of Pulmonary Gas Exchange by "Circulatory Equivalents" in Chronic Heart Failure

Peak ratios of pulmonary gas-exchange to ventilation during exercise (V˙O2/V˙E and V˙CO2/V˙E, termed "circulatory equivalents") are sensitive to heart failure (HF) severity, likely reflecting low and/or poorly distributed pulmonary perfusion. We tested whether peak V˙O2/V˙E and V˙CO2/V˙E would: (1) distinguish HF patients from controls; (2) be independent of incremental exercise protocol; and (3) correlate with lactate threshold (LT) and ventilatory compensation point (VCP), respectively.Twenty-four HF patients (61±11 years) with reduced ejection fraction (31±8%) and 11 controls (63±7 years) performed ramp-incremental cycle ergometry. Eighteen HF patients also performed slow (5±1 W/min), medium (9±4 W/min), and fast (19±6 W/min) ramps. Peak V˙O2/V˙E and V˙CO2/V˙E from X-Y plot, and LT and VCP from 9-panel plot, were determined by 2 independent, blinded, assessors. Peak V˙O2/V˙E (31.2±4.4 versus 41.8±4.8 mL/L; P<0.0001) and V˙CO2/V˙E (29.3±3.0 versus 36.9±4.0 mL/L; P<0.0001) were lower in HF than controls. Within individuals, there was no difference across 3 ramp rates in peak V˙O2/V˙E (P=0.62) or V˙CO2/V˙E (P=0.97). Coefficient of variation (CV) in peak V˙O2/V˙E was lower than for LT (5.1±2.1% versus 8.2±3.7%; P=0.014), and coefficient of variation in peak V˙CO2/V˙E was lower than for VCP (3.3±1.8% versus 8.7±4.2%; P<0.001). In all participants, peak V˙O2/V˙E was correlated with, but occurred earlier than, LT (r2=0.94; mean bias, -0.11 L/min), and peak V˙CO2/V˙E was correlated with, but occurred earlier than, VCP (r2=0.98; mean bias -0.08 L/min).Peak circulatory equivalents during exercise are strongly associated with (but not identical to) LT and VCP. Peak circulatory equivalents are reliable, objective, effort-independent indices of gas-exchange abnormality in HF

Human exercise-induced circulating progenitor cell mobilization is nitric oxide-dependent and is blunted in South Asian men

This article is available open access through the publisher’s website. Copyright @ 2010 American Heart Foundation.Objective— Circulating progenitor cells (CPC) have emerged as potential mediators of vascular repair. In experimental models, CPC mobilization is critically dependent on nitric oxide (NO). South Asian ethnicity is associated with reduced CPC. We assessed CPC mobilization in response to exercise in Asian men and examined the role of NO in CPC mobilization per se. Methods and Results— In 15 healthy, white European men and 15 matched South Asian men, CPC mobilization was assessed during moderate-intensity exercise. Brachial artery flow-mediated vasodilatation was used to assess NO bioavailability. To determine the role of NO in CPC mobilization, identical exercise studies were performed during intravenous separate infusions of saline, the NO synthase inhibitor l-NMMA, and norepinephrine.  Flow-mediated vasodilatation (5.8%±0.4% vs 7.9%±0.5%; P=0.002) and CPC mobilization (CD34+/KDR+ 53.2% vs 85.4%; P=0.001; CD133+/CD34+/KDR+ 48.4% vs 73.9%; P=0.05; and CD34+/CD45− 49.3% vs 78.4; P=0.006) was blunted in the South Asian group. CPC mobilization correlated with flow-mediated vasodilatation and l-NMMA significantly reduced exercise-induced CPC mobilization (CD34+/KDR+ −3.3% vs 68.4%; CD133+/CD34+/KDR+ 0.7% vs 71.4%; and CD34+/CD45− −30.5% vs 77.8%; all P<0.001). Conclusion— In humans, NO is critical for CPC mobilization in response to exercise. Reduced NO bioavailability may contribute to imbalance between vascular damage and repair mechanisms in South Asian men.British Heart Foundatio

Exercise Ventilatory Irregularity can be quantified by Approximate Entropy to detect Breathing Pattern Disorder

Background Breathing pattern disorder (BPD) is a prevalent cause of exertional dyspnea and yet there is currently no reliable objective measure for its diagnosis. We propose that statistical analysis of ventilatory irregularity, quantified by approximate entropy (ApEn), could be used to detect BPD when applied to cardiopulmonary exercise test (CPET) data. We hypothesized that ApEn of ventilatory variables (tidal volume (VT), breathing frequency (Bf), minute ventilation (VE)) would be greater, i.e. more irregular, in patients with BPD than healthy controls. Methods We evaluated ventilatory ApEn in 20 adults (14 female) with exertional dyspnoea, undergoing CPET and independently diagnosed with BPD by a specialist respiratory physiotherapist. Data were compared with 15 age- gender- and BMI-matched controls. ApEn for VT, Bf and VE were calculated for an incremental cycle exercise test. Results Patients with BPD more frequently rated breathlessness as the reason for exercise limitation and had a lower mean (SD) peak oxygen uptake compared with controls: 80 (18) vs. 124 (27) % predicted (P  0.88, conferred a sensitivity and specificity of 70% and 87% respectively, for detection of BPD. Conclusions Non-linear statistical interrogation of CPET-acquired ventilatory data has utility in the detection of BPD. A simple calculation of approximate entropy of ventilation, during an incremental cardiopulmonary exercise test, provides a quantitative method to detect BPD