Skeletal Muscle Energetics, Acid-Base Equilibrium and Lactate Metabolism in Patients with Severe Hypercapnia and Hypoxemia

doi:10.1378/chest.92.5.883

Chest

Volume 92, Issue 5, November 1987, Pages 883-887

https://doi.org/10.1378/chest.92.5.883 Get rights and content

Quadriceps femoris muscle needle biopsies were performed in ten patients with chronic obstructive pulmonary disease and acute respiratory failure and in ten age- and sex-matched healthy control subjects. The main indices of skeletal muscle cell energy metabolism, intracellular acid-base equilibrium and lactate metabolism were evaluated. Reduced ATP and phosphocreatine content, intracellular acidosis related to hypercapnia, increased muscle lactate without alterations of the muscle lactate concentration gradient were observed in the skeletal muscle of the hypercapnic-hypoxemic COPD patients studied, in which group no correlation was found between hypoxia and energy or lactate metabolism parameters. These results suggest that an overall derangement of cell energy metabolism and acid-base equilibrium is present in severely hypercapnic-hypoxemic chronic obstructive pulmonary disease and that in this condition skeletal muscle seems to metabolize anaerobically—even though, in addition to hypoxia, other factors interfering with both cell energy and lactate metabolism are likely to be present.

Section snippets

Patients

Ten COPD patients (nine men and one woman) who ranged in age from 52 to 75 yr (mean, 62 ± 3 yr SEM) were admitted to a Pulmonary Intensive Care Unit for ARF. Blood gas measurements were as follows: arterial carbon dioxide tension (PaCO₂), 72 ± 4 mm Hg SEM, range, 54 to 99 mm Hg; arterial oxygen þressure (PaO₂), 38 ± 2 mm Hg SEM, range, 28 to 50 mm Hg; pHa, 7.32 ± 0.02 SEM, range, 7.25 to 7.37.

All patients had had an acute exacerbation of their underlying disease (two to eight days prior to

STATISTICS

The Mann-Whitney test was used to assess the statistical significance of differences between control subjects and COPD patients.¹⁰

Standard techniques of linear regression and correlation also were utilized.

RESULTS

Table 1 shows energy metabolism parameters and intracellular acid-base equilibrium indices of COPD patients with ARF.

A marked decrease of both muscle ATP and PCr contents as well as a significant decrease in TAN, the ATP-ADP ratio and ECP were found. No differences in ADP, AMP, or total Cr content were found between patients and controls.

Intracellular pH values were significantly (p<0.001) reduced and correlated to PaCO₂ values (pH_i = 7.76 – 0.0138 PaCO₂, r = 0.77, n = 10, p<0.01), but not to

DISCUSSION

Low pH_i, reduced ATP and PCr contents, and increased muscle and Lact_fvp values characterize the skeletal muscle of the hypercapnic-hypoxemic COPD patients considered in our study.

The finding of an intracellular acidosis related to PaCO₂ confirms the results of a previous study on a comparable group of subjects with COPD and ARF.²

The extent of the decrease of ATP and PCr content (about 30 to 35 percent of control values) is comparable to that found both in subjects with cardiogenic shock or

ACKNOWLEDGMENTS

We would like to express our gratitude to Mrs. Nancy Birch-Podini for skillful assistance in preparing the manuscript.

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Restrictions in ATP diffusion within sarcomeres can provoke ATP-depleted zones impairing exercise capacity in chronic obstructive pulmonary disease
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To this end we implemented a model of anisotropic two-dimensional diffusion of metabolites within sarcomeres (Eq. (10); Fig. 1A). This model assumes that aerobically synthesized ATP homogeneously distributes throughout the cytosol, outside of sarcomeres, at the level of 8.2 mM [32,51–53]. The cytosolic ATP diffuses radially to the center (Dr) as well as in the longitudinal direction (Dx) within a sarcomere, where it is utilized by mATPases.
Chronic obstructive pulmonary disease (COPD) is characterized by the inability of patients to sustain a high level of ventilation resulting in perceived exertional discomfort and limited exercise capacity of leg muscles at average intracellular ATP levels sufficient to support contractility.
Myosin ATPase activity in biopsy samples from healthy and COPD individuals was implemented as a local nucleotide sensor to determine ATP diffusion coefficients within myofibrils. Ergometric parameters clinically measured during maximal exercise tests in both groups were used to define the rates of myosin ATPase reaction and aerobic ATP re-synthesis. The obtained parameters in combination with AK- and CK-catalyzed reactions were implemented to compute the kinetic and steady-state spatial ATP distributions within control and COPD sarcomeres.
The developed reaction–diffusion model of two-dimensional sarcomeric space identified similar, yet extremely low nucleotide diffusion in normal and COPD myofibrils. The corresponding spatio-temporal ATP distributions, constructed during imposed exercise, predicted in COPD sarcomeres a depletion of ATP in the zones of overlap between actin and myosin filaments along the center axis at average cytosolic ATP levels similar to healthy muscles.
ATP-depleted zones can induce rigor tension foci impairing muscle contraction and increase a risk for sarcomere damages. Thus, intra-sarcomeric diffusion restrictions at limited aerobic ATP re-synthesis can be an additional risk factor contributing to the muscle contractile deficiency experienced by COPD patients.
This study demonstrates how restricted substrate mobility within a cellular organelle can provoke an energy imbalance state paradoxically occurring at abounding average metabolic resources.
The effect of dietary nitrate supplementation on the oxygen cost of cycling, walking performance and resting blood pressure in individuals with chronic obstructive pulmonary disease: A double blind placebo controlled, randomised control trial
2015, Nitric Oxide - Biology and Chemistry
Citation Excerpt :
Some nitrite is absorbed into the circulation where it acts as a storage pool for subsequent NO production [14]. The conversion of nitrite to NO is expedited in conditions of acidosis [21] or hypoxemia [14] which often occur in the exercising muscle of individuals with COPD [22]. In many individuals with COPD, functional capacity is reduced to a level where activities of daily living may impose a challenge due to an energy requirement representing a high fraction of their maximal oxygen uptake.
Chronic obstructive pulmonary disease (COPD) results in exercise intolerance. Dietary nitrate supplementation has been shown to lower blood pressure (BP), reduce the oxygen cost of exercise, and enhance exercise tolerance in healthy volunteers. This study assessed the effects of dietary nitrate on the oxygen cost of cycling, walking performance and BP in individuals with mild–moderate COPD.
Thirteen patients with mild–moderate COPD were recruited. Participants consumed 70 ml of either nitrate-rich (6.77 mmol nitrate; beetroot juice) or nitrate-depleted beetroot juice (0.002 mmol nitrate; placebo) twice a day for 2.5 days, with the final supplement ~3 hours before testing. BP was measured before completing two bouts of moderate-intensity cycling, where pulmonary gas exchange was measured throughout. The six-minute walk test (6MWT) was completed 30 minutes subsequent to the second cycling bout.
Plasma nitrate concentration was significantly elevated following beetroot juice vs. placebo (placebo; 48 ± 86 vs. beetroot juice; 215 ± 84 µM, P = 0.002). No significant differences were observed between placebo vs. beetroot juice for oxygen cost of exercise (933 ± 323 vs. 939 ± 302 ml: min⁻¹; P = 0.88), distance covered in the 6MWT (456 ± 86 vs. 449 ± 79 m; P = 0.37), systolic BP (123 ± 14 vs. 123 ± 14 mmHg; P = 0.91), or diastolic BP (77 ± 9 vs. 79 ± 9 mmHg; P = 0.27).
Despite a large rise in plasma nitrate concentration, two days of nitrate supplementation did not reduce the oxygen cost of moderate intensity cycling, increase distance covered in the 6MWT, or lower BP.
Diagnostic usefulness of B-type natriuretic peptide and functional consequences of muscle alterations in COPD and chronic heart failure
2006, Chest
Citation Excerpt :
Quadriceps atrophy is associated with decreased muscle strength in both conditions.45,52 More importantly, skeletal muscle abnormalities promote muscle fatigue during exercise that leads patients with severe chronic heart failure or severe COPD to stop exercising before they exhaust their cardiac or pulmonary reserve.53,54 Thus, skeletal muscle abnormalities tend to limit maximal functional capacity in patients with advanced COPD or chronic heart failure independently from the primary process.55,55,56,57
COPD affects up to one third of patients with chronic heart failure. The coexistence of COPD and chronic heart failure presents clinicians with diagnostic and therapeutic challenges. Measurement of B-type natriuretic peptide plasma levels facilitates the diagnosis of acute dyspnea in patients known to have both COPD and chronic heart failure. Patients with COPD or chronic heart failure have skeletal muscle abnormalities that limit functional capacity independently from primary organ failure. Exercise training reverses skeletal muscle abnormalities in patients with COPD or chronic heart failure and may be particularly indicated in patients with coexistent COPD and chronic heart failure.
Limiting factors of exercise capacity in patients with COPD
2004, Revista Portuguesa de Pneumologia
A Doença Pulmonar Obstrutiva Crónica (DPOC) é uma das principais causas de morbilidade e mortalidade em todo o mundo. Os doentes com DPOC moderada/grave apresentam, com frequência, intolerância ao exercício físico nas actividades da vida diária, o que afecta a sua qualidade de vida. São apontadas na literatura diversas causas para a diminuição da tolerância ao exercício físico: a obstrução brônquica, a hiperinsuflação pulmonar, a fraqueza dos músculos respiratórios e dos músculos periféricos, entre outras.
O presente trabalho teve por objectivo identificar os factores potencialmente implicados na limitação do exercício num grupo de doentes com DPOC moderada a grave.
Estudaram-se 24 doentes do sexo masculino com 64,13 + 8,46 anos (46-83 anos), FEV₁:46,96 + + 12,99% do teórico, FRC: 144,71 + 26,86% do teórico, DLCO: 69,88 + 16,49 % teórico, PaO₂:78,25 + 7,82 mmHg, PaCO₂:40,78 + 4,28 mmHg. Os doentes foram submetidos a um teste incremental progressivo limitado por sintomas em cicloergómetro. Correlacionaram-se os parâmetros funcionais em repouso e no exercício com o consumo máximo de oxigénio, a carga suportada e a duração da prova.
Os factores que contribuíram de forma mais significativa para a limitação do desempenho no exercício foram a alteração das trocas gasosas, a limitação ventilatória e um menor índice de massa corporal na avaliação nutricional.
A hiperinsuflação pulmonar avaliada em repouso não se correlacionou com o desempenho no exercício. Quanto à hiperinsuflação pulmonar no exercício, contribuiu de forma importante para a intolerância ao esforço, através da restrição progressiva à expansão do volume corrente necessária para fazer face ao aumento das exigências metabólicas do exercício.
Os parâmetros funcionais avaliados em repouso não se correlacionaram com o desempenho no exercício, o que revela a importância das provas de esforço cardiorrespiratórias para a detecção dos factores que limitam o exercício em cada doente.
A identificação dos factores limitativos do desempenho no exercício poderá contribuir significativamente para a definição da estratégia terapêutica a adoptar nos doentes com DPOC.
REV PORT PNEUMOL 2004; X (1): 9-61
Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality worldwide. Moderate to severe COPD patients demonstrate severe impairments in exercise performance in daily activities, significantly affec-ting their quality of life. There are several causes for this limitation found in literature: air-flow limitation, lung hyperinflation, respiratory and peripheral muscles weakness, among others.
In this study we intended to identify the potentially relevant factors that influence exercise performance in a group of moderate to severe COPD patients.
We studied 24 male patients, 64,13 + 8,46 years old (46-83 years), FEV₁:46,96 + 12,99% predicted, FRC: 144,71 + 26,86% predicted, DLCO: 69,88 + 16,49 % predicted, PaO₂:78,25 + 7,82 mmHg, PaCO₂:40,78 + 4,28 mmHg. Patients performed an incremental symptom-limited cycle exercise. We correlated rest and exercise lung function parameters with peak oxygen uptake, maximal work rate and time span to exertion.
The main contributors to exercise limitation were gas exchange abnormalities, ventilatory limitation and smaller values of body mass index.
Rest lung hyperinflation didn’t correlate with exercise performance. Dynamic exercise hyperinflation contributed greatly to exercise intolerance, through progressive restriction to tidal volume expansion necessary to deal with increasing exercise metabolic demands.
Rest lung function parameters didn’t correlate with exercise performance, stressing the importance of cardio-pulmonary exercise testing in the detection of exercise limitation factors in each patient.
The identification of exercise limitation factors will certainly contribute to towards defining the best therapeutic approach in COPD patients.
REV PORT PNEUMOL 2004; X (1): 9-61
La Bronchopneumopathie Chronique Obstructive (BPCO) est une cause majeure de morbidité et de mortalité dans le monde. Les patients BPCO modérés à sévères montrent d’importantes limitations à l’exercice physique dans leurs activités journalières, affectant de manière significative leur qualité de vie. Il existe plusieurs causes à cette limitation identifiées dans la littérature: les limitations des débits ventilés, l’hyperinflation pulmonaire, la faiblesse des muscles respiratoires et périphériques, parmi d’autres.
Le but de cette étude etait d’identifier les facteurs en relation possible avec la limitation de la performance physique chez un groupe de patients BPCO modérés à sévères.
Nous avons étudié 24 sujets masculins, âgés de 64,13 + 8,46 ans (de 46-83 ans), FEV₁:46,96 + 12,99%, FRC: 144,71 + 26,86%, DLCO: 69,88 + 16,49 % (% de la valeur prédite), PaO₂:78,25 + 7,82 mmHg, PaCO₂:40,78 + 4,28 mmHg. Les patients ont réalisé un exercice à charge croissante sur bicyclette ergométrique jusqu’à la limite imposée par les symptômes. Nous avons comparé les paramètres de la fonction pulmonaire au repos et à l’exercice avec la consommation maximale d’oxygène, le travail maximal supporté et le temps d´épreuve jusqu´à l´exhaustion.
Les principaux facteurs limitant l’exercice physique sont les anomalies des échanges gazeux, la limitation ventilatoire et de faibles valeurs de l’index de masse corporelle.
L’hyperinflation au repos n’est pas corrélée avec la performance physique. L’hyperinflation dynamique contribue de manière importante à l’intolérance à l’exercice, en raison d’une restriction progressive de l’expansion du volume courant nécessaire à une adaptation à la demande métabolique croissante liée à l’exercice.
Les paramètres de la fonction pulmonaire au repos ne sont pas corrélés avec la performance physique, attirant ainsi l’attention sur l’importance du test cardio-respiratoire à l’effort pour détecter les facteurs limitatifs de l’exercice de chaque patient.
L’identification des facteurs limitants l’exercice contribuera certainement à préciser la meilleure approche thérapeutique du patient BPCO.
REV PORT PNEUMOL 2004; X (1): 9-61
Muscle strength and exercise kinetics in COPD patients with a normal fat-free mass index are comparable to control subjects
2003, Chest
Citation Excerpt :
However, in that report patients with a wide range of airflow limitations were studied, thereby including many patients with mild and moderate COPD who more closely resemble healthy individuals. In contrast, our patients had more severe airflow limitation and were more representative of those patients in whom the findings of muscle biopsy specimen tests and physiologic studies have suggested the presence of peripheral muscle abnormalities.2345612 It is possible that the lower inspiratory pressures, coupled with the inability to increase ventilation, contribute to dyspnea at peak exercise.27
This study was designed to investigate the extent of clinical muscle dysfunction in stable patients with COPD who were attending an out-patient pulmonary clinic compared with that of age-matched control subjects without COPD.
Respiratory muscle and hand grip strength, steady-state O₂ kinetics, and body composition were measured in 32 patients with COPD (19 women) [mean (± SD) FEV₁, 38 ± 11% predicted] and 36 age-matched control subjects (13 women).
Measurements of handgrip force (mean, 97 ± 32% vs 106 ± 26% predicted, respectively), maximal expiratory pressure (mean, 57 ± 33% vs 61 ± 22% predicted, respectively), steady-state O₂ kinetics (mean τ, 72 ± 34 s vs 78 ± 37 s, respectively) and steady-state CO₂ kinetics (mean τ, 77 ± 38 s vs 65 ± 32 s, respectively) at submaximal exercise were similar in patients and control subjects. All the subjects, except for one female COPD patient, had a normal fat-free mass index (FFMI), although on average the FFMI was lower in male patients (19.8 ± 2.8) than in male control subjects (23.0 ± 2.8; p < 0.01).
In patients with COPD who were attending a regular outpatient pulmonary clinic, there was no evidence of reduced upper extremity and expiratory muscle strength or prolonged O₂ and CO₂ kinetics during isowork submaximal cardiopulmonary exercise compared to healthy, age-matched control subjects. Also, a normal body composition was found in nearly all COPD patients. This argues against the existence of a clinically significant systemic myopathy in most stable patients with severe COPD and normal FFMI.
Peripheral muscle dysfunction in chronic obstructive pulmonary disease
2000, Clinics in Chest Medicine
Citation Excerpt :
atrophy of type I and IIa fibers124 ↓adenosine triphosphate (ATP) concentration36,41 The quadriceps is the most commonly studied peripheral muscle because it is readily accessible and because it is a primary effector muscle of ambulation.
As their life expectancy has been prolonged with improved medical care, patients with chronic obstructive pulmonary disease (COPD) frequently develop systemic complications of their disease. These complications include osteoporosis, depression, and peripheral muscle dysfunction² characterized by atrophy, weakness, and low oxidative capacity. These muscle changes have been associated with exercise intolerance,⁴⁴ poor quality of life¹¹⁵ and reduced survival,108, 127 which occur independently of the impairment in lung function. Physicians dealing with patients with advanced COPD face the challenge of finding innovative ways to improve their patients' level of function despite the irreversible impairment of the primarily diseased organ. In this article, the evidence for peripheral muscle dysfunction in patients with COPD and the possible clinical implications of this problem are discussed. The available therapeutic options for improving peripheral muscle function are also considered.

View all citing articles on Scopus

Supported in part by CNR grant 0002504/11508323.

Manuscript received November 24; revision accepted March 13.

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Chest

Skeletal Muscle Energetics, Acid-Base Equilibrium and Lactate Metabolism in Patients with Severe Hypercapnia and Hypoxemia

Section snippets

Patients

STATISTICS

RESULTS

DISCUSSION

ACKNOWLEDGMENTS

J Biol Chem

Metabolism

J Biol Chem

Kidney Int

Muscle metabolism in patients with chronic obstructive lung disease and acute respiratory failure

Clin Sci Mol Med

Intracellular acid-base and electrolyte metabolism in skeletal muscle of patients with chronic obstructive lung disease and respiratory failure

Clin Sci

Muscle electrolytes in man

Scand J Clin Lab Invest

Determination of the true chloride content of biological fluids and tissues

Anal Chem

Intracellular pH and bicarbonate concentration as determined in biopsy samples from the quadriceps muscle of man at rest

Clin Sci Mol Med

Intracellular bicarbonate and pH determination in rat skeletal muscle from acid-labile CO2 measurement by dead-stop end-point potentiometric titrations

Eur Rev Med Pharmacol Sci

Glycogen, glycolytic intermediate and high energy phosphates in biopsy samples of m. quadriceps femoris of man at rest: methods and variance of values

Scand J Clin Lab Invest

The energy charge of the adenylate pool as a regulatory parameter: interaction with feed-back modifiers

Biochemistry

Non-parametric statistics

Intracellular bicarbonate and pH determination in rat skeletal muscle from acid-labile CO₂ measurement by dead-stop end-point potentiometric titrations