Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting.

Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic disease with several comorbidities. Among them, skeletal muscle dysfunction affects around 20% of COPD patients and is associated with higher morbidity and mortality. Although the histological alterations are well characterized, including myofiber atrophy, a decreased proportion of slow-twitch myofibers, and a decreased capillarization and oxidative phosphorylation capacity, the molecular basis for muscle atrophy is complex and remains partly unknown. Major difficulties lie in patient heterogeneity, accessing patients' samples, and complex multifactorial process including extrinsic mechanisms, such as tobacco smoke or disuse, and intrinsic mechanisms, such as oxidative stress, hypoxia, or systemic inflammation. Muscle wasting is also a highly dynamic process whose investigation is hampered by the differential protein regulation according to the stage of atrophy. In this review, we report and discuss recent data regarding the molecular alterations in COPD leading to impaired muscle mass, including inflammation, hypoxia and hypercapnia, mitochondrial dysfunction, diverse metabolic changes such as oxidative and nitrosative stress and genetic and epigenetic modifications, all leading to an impaired anabolic/catabolic balance in the myocyte. We recapitulate data concerning skeletal muscle dysfunction obtained in the different rodent models of COPD. Finally, we propose several pathways that should be investigated in COPD skeletal muscle dysfunction in the future.

Cellular interplay in skeletal muscle regeneration and wasting: insights from animal models.

Skeletal muscle wasting, whether related to physiological ageing, muscle disuse or to an underlying chronic disease, is a key determinant to quality of life and mortality. However, cellular basis responsible for increased catabolism in myocytes often remains unclear. Although myocytes represent the vast majority of skeletal muscle cellular population, they are surrounded by numerous cells with various functions. Animal models, mostly rodents, can help to decipher the mechanisms behind this highly dynamic process, by allowing access to every muscle as well as time-course studies. Satellite cells (SCs) play a crucial role in muscle regeneration, within a niche also composed of fibroblasts and vascular and immune cells. Their proliferation and differentiation is altered in several models of muscle wasting such as cancer, chronic kidney disease or chronic obstructive pulmonary disease (COPD). Fibro-adipogenic progenitor cells are also responsible for functional muscle growth and repair and are associated in disease to muscle fibrosis such as in chronic kidney disease. Other cells have recently proven to have direct myogenic potential, such as pericytes. Outside their role in angiogenesis, endothelial cells and pericytes also participate to healthy muscle homoeostasis by promoting SC pool maintenance (so-called myogenesis-angiogenesis coupling). Their role in chronic diseases muscle wasting has been less studied. Immune cells are pivotal for muscle repair after injury: Macrophages undergo a transition from the M1 to the M2 state along with the transition between the inflammatory and resolutive phase of muscle repair. T regulatory lymphocytes promote and regulate this transition and are also able to activate SC proliferation and differentiation. Neural cells such as terminal Schwann cells, motor neurons and kranocytes are notably implicated in age-related sarcopenia. Last, newly identified cells in skeletal muscle, such as telocytes or interstitial tenocytes could play a role in tissular homoeostasis. We also put a special focus on cellular alterations occurring in COPD, a chronic and highly prevalent respiratory disease mainly linked to tobacco smoke exposure, where muscle wasting is strongly associated with increased mortality, and discuss the pros and cons of animal models versus human studies in this context. Finally, we discuss resident cells metabolism and present future promising leads for research, including the use of muscle organoids.

Efficacy of 12 weeks oral beta-alanine supplementation in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Beta-alanine (BA) supplementation increases muscle carnosine, an abundant endogenous antioxidant and pH buffer in skeletal muscle. Carnosine loading promotes exercise capacity in healthy older adults. As patients with chronic obstructive pulmonary disease (COPD) suffer from elevated exercise-induced muscle oxidative/carbonyl stress and acidosis, and from reduced muscle carnosine stores, it was investigated whether BA supplementation augments muscle carnosine and induces beneficial changes in exercise capacity, quadriceps function, and muscle oxidative/carbonyl stress in patients with COPD. METHODS: In this double-blind, randomized, placebo (PL)-controlled trial (clinicaltrials.gov identifier: NCT02770417), 40 patients (75% male) with COPD (mean ± standard deviation: age 65 ± 6 years; FEV1 % predicted 55 ± 14%) were assigned to 12 weeks oral BA or PL supplementation (3.2 g/day). The primary outcome, i.e. muscle carnosine, was quantified from m. vastus lateralis biopsies obtained before and after intervention. Co-primary outcomes, i.e. incremental and constant work rate cycle capacity, were also assessed. Linear mixed model analyses were performed. Compliance with and side effects of supplement intake and secondary outcomes (quadriceps strength and endurance, and muscle oxidative/carbonyl stress) were also assessed. RESULTS: Beta-alanine supplementation increased muscle carnosine in comparison with PL in patients with COPD (mean difference [95% confidence interval]; +2.82 [1.49-4.14] mmol/kg wet weight; P < 0.001). Maximal incremental cycling capacity (VO2 peak: +0.5 [-0.7 to 1.7] mL/kg/min; P = 0.384, Wpeak: +5 [-1 to 11] W; P = 0.103) and time to exhaustion on the constant work rate cycle test (+28 [-179 to 236] s; P = 0.782) did not change significantly. Compliance with supplement intake was similar in BA (median (quartile 1-quartile 3); 100 (98-100)%) and PL (98 (96-100)%) (P = 0.294) groups, and patients did not report side effects possibly related to supplement intake. No change was observed in secondary outcomes. CONCLUSIONS: Beta-alanine supplementation is efficacious in augmenting muscle carnosine (+54% from mean baseline value) without side effects in patients with COPD in comparison with PL. However, accompanied beneficial changes in exercise capacity, quadriceps function, and muscle oxidative/carbonyl stress were not observed.

Standardization of the assessment process within telerehabilitation in chronic diseases: a scoping meta-review.

BACKGROUND: Telerehabilitation (TR) interventions are receiving increasing attention. They have been evaluated in various scientific areas through systematic reviews. However, there is a lack of data on how to standardize assessment and report on their domains to guide researchers across studies and bring together the best evidence to assess TR for chronic diseases. AIMS AND OBJECTIVES: The aim of this study was to identify domains of assessment in TR and to qualitatively and quantitatively analyze how and when they are examined to gain an overview of assessment in chronic disease. METHODS: A scoping meta-review was carried out on 9 databases and gray literature from 2009 to 2019. The keyword search strategy was based on "telerehabilitation", "evaluation", "chronic disease" and their synonyms. All articles were subjected to qualitative analysis using the Health Technology Assessment (HTA) Core Model prior to further analysis and narrative synthesis. RESULTS: Among the 7412 identified articles, 80 studies met the inclusion criteria and addressed at least one of the noncommunicable diseases (NCD) categories of cardiovascular disease (cardiovascular accidents), cancer, chronic respiratory disease, diabetes, and obesity. Regarding the domains of assessment, the most frequently occurring were "social aspect" (n = 63, 79%) (e.g., effects on behavioral changes) and "clinical efficacy" (n = 53, 66%), and the least frequently occurring was "safety aspects" (n = 2, 3%). We also identified the phases of TR in which the assessment was conducted and found that it most commonly occurred in the pilot study and randomized trial phases and least commonly occurred in the design, pretest, and post-implementation phases. CONCLUSIONS: Through the HTA model, this scoping meta-review highlighted 10 assessment domains which have not been studied with the same degree of interest in the recent literature. We showed that each of these assessment domains could appear at different phases of TR development and proposed a new cross-disciplinary and comprehensive method for assessing TR interventions. Future studies will benefit from approaches that leverage the best evidence regarding the assessment of TR, and it will be interesting to extend this assessment framework to other chronic diseases.

Skeletal Muscle Phenotype in Patients Undergoing Long-Term Hemodialysis Awaiting Kidney Transplantation.

BACKGROUND AND OBJECTIVES: Age and comorbidity-related sarcopenia represent a main cause of muscle dysfunction in patients on long-term hemodialysis. However, recent findings suggest muscle abnormalities that are not associated with sarcopenia. The aim of this study was to isolate functional and cellular muscle abnormalities independently of other major confounding factors, including malnutrition, age, comorbidity, or sedentary lifestyle, which are common in patients on maintenance hemodialysis. To overcome these confounding factors, alterations in skeletal muscle were analyzed in highly selected patients on long-term hemodialysis undergoing kidney transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 22 patients on long-term hemodialysis scheduled for kidney transplantation with few comorbidities, but with a long-term uremic milieu exposure, and 22 age, sex, and physical activity level frequency-matched control participants were recruited. We compared biochemical, functional, and molecular characteristics of the skeletal muscle using maximal voluntary force and endurance of the quadriceps, 6-minute walking test, and muscle biopsy of vastus lateralis. For statistical analysis, mean comparison and multiple regression tests were used. RESULTS: In patients on long-term hemodialysis, muscle endurance was lower, whereas maximal voluntary force was not significantly different. We observed a transition from type I (oxidative) to type II (glycolytic) muscle fibers, and an alteration of mitochondrial structure (swelling) without changes in DNA content, genome replication (peroxisome proliferator activator receptor γ coactivator-1α and mitochondrial transcription factor A), regulation of fusion (mitofusin and optic atrophy 1), or fission (dynamin-related protein 1). Notably, there were autophagosome structures containing glycogen along with mitochondrial debris, with a higher expression of light chain 3 (LC3) protein, indicating phagophore formation. This was associated with a greater conversion of LC3-I to LC3-II and the expression of Gabaralp1 and Bnip3l genes involved in mitophagy. CONCLUSIONS: In this highly selected long-term hemodialysis population, a low oxidative phenotype could be defined by a poor endurance, a fiber-type switch, and an alteration of mitochondria structure, without evidence of sarcopenia. This phenotype could be related to uremia through the activation of autophagy/mitophagy. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02794142 and NCT02040363.

Hypoxic Conditions Promote Rhythmic Contractile Oscillations Mediated by Voltage-Gated Sodium Channels Activation in Human Arteries.

Arterial smooth muscle exhibits rhythmic oscillatory contractions called vasomotion and believed to be a protective mechanism against tissue hypoperfusion or hypoxia. Oscillations of vascular tone depend on voltage and follow oscillations of the membrane potential. Voltage-gated sodium channels (Nav), responsible for the initiation and propagation of action potentials in excitable cells, have also been evidenced both in animal and human vascular smooth muscle cells (SMCs). For example, they contribute to arterial contraction in rats, but their physiopathological relevance has not been established in human vessels. In the present study, we investigated the functional role of Nav in the human artery. Experiments were performed on human uterine arteries obtained after hysterectomy and on SMCs dissociated from these arteries. In SMCs, we recorded a tetrodotoxin (TTX)-sensitive and fast inactivating voltage-dependent INa current. Various Nav genes, encoding α-subunit isoforms sensitive (Nav 1.2; 1.3; 1.7) and resistant (Nav 1.5) to TTX, were detected both in arterial tissue and in SMCs. Nav channels immunostaining showed uniform distribution in SMCs and endothelial cells. On arterial tissue, we recorded variations of isometric tension, ex vivo, in response to various agonists and antagonists. In arterial rings placed under hypoxic conditions, the depolarizing agent KCl and veratridine, a specific Nav channels agonist, both induced a sustained contraction overlaid with rhythmic oscillations of tension. After suppression of sympathetic control either by blocking the release of catecholamine or by antagonizing the target adrenergic response, rhythmic activity persisted while the sustained contraction was abolished. This rhythmic activity of the arteries was suppressed by TTX but, in contrast, only attenuated by antagonists of calcium channels, Na+/Ca2+ exchanger, Na+/K+-ATPase and the cardiac Nav channel. These results highlight the role of Nav as a novel key element in the vasomotion of human arteries. Hypoxia promotes activation of Nav channels involved in the initiation of rhythmic oscillatory contractile activity.

Impaired training-induced angiogenesis process with loss of pericyte-endothelium interactions is associated with an abnormal capillary remodelling in the skeletal muscle of COPD patients.

Chronic obstructive pulmonary disease (COPD) is associated with exercise intolerance and limits the functional gains in response to exercise training in patients compared to sedentary healthy subjects (SHS). The blunted skeletal muscle angiogenesis previously observed in COPD patients has been linked to these limited functional improvements, but its underlying mechanisms, as well as the potential role of oxidative stress, remain poorly understood. Therefore, we compared ultrastructural indexes of angiogenic process and capillary remodelling by transmission electron microscopy in 9 COPD patients and 7 SHS after 6 weeks of individualized moderate-intensity endurance training. We also assessed oxidative stress by plasma-free and esterified isoprostane (F2-IsoP) levels in both groups. We observed a capillary basement membrane thickening in COPD patients only (p = 0.008) and abnormal variations of endothelial nucleus density in response to exercise training in these patients when compared to SHS (p = 0.042). COPD patients had significantly fewer occurrences of pericyte/endothelium interdigitations, a morphologic marker of capillary maturation, than SHS (p = 0.014), and significantly higher levels of F2-IsoP (p = 0.048). Last, the changes in pericyte/endothelium interdigitations and F2-IsoP levels in response to exercise training were negatively correlated (r = - 0.62, p = 0.025). This study is the first to show abnormal capillary remodelling and to reveal impairments during the whole process of angiogenesis (capillary creation and maturation) in COPD patients. TRIAL REGISTRATION: NCT01183039 & NCT01183052, both registered 7 August 2010 (retrospectively registered).

Additional Effects of Nutritional Antioxidant Supplementation on Peripheral Muscle during Pulmonary Rehabilitation in COPD Patients: A Randomized Controlled Trial.

BACKGROUND: Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD) is not fully reversed by exercise training. Antioxidants are critical for muscle homeostasis and adaptation to training. However, COPD patients experience antioxidant deficits that worsen after training and might impact their muscle response to training. Nutritional antioxidant supplementation in combination with pulmonary rehabilitation (PR) would further improve muscle function, oxidative stress, and PR outcomes in COPD patients. METHODS: Sixty-four COPD patients admitted to inpatient PR were randomized to receive 28 days of oral antioxidant supplementation targeting the previously observed deficits (PR antioxidant group; α-tocopherol: 30 mg/day, ascorbate: 180 mg/day, zinc gluconate: 15 mg/day, selenomethionine: 50 µg/day) or placebo (PR placebo group). PR consisted of 24 sessions of moderate-intensity exercise training. Changes in muscle endurance (primary outcome), oxidative stress, and PR outcomes were assessed. RESULTS: Eighty-one percent of the patients (FEV1 = 58.9 ± 20.0%pred) showed at least one nutritional antioxidant deficit. Training improved muscle endurance in the PR placebo group (+37.4 ± 45.1%, p < 0.001), without additional increase in the PR antioxidant group (-6.6 ± 11.3%; p = 0.56). Nevertheless, supplementation increased the α-tocopherol/γ-tocopherol ratio and selenium (+58 ± 20%, p < 0.001, and +16 ± 5%, p < 0.01, respectively), muscle strength (+11 ± 3%, p < 0.001), and serum total proteins (+7 ± 2%, p < 0.001), and it tended to increase the type I fiber proportion (+32 ± 17%, p = 0.07). The prevalence of muscle weakness decreased in the PR antioxidant group only, from 30.0 to 10.7% (p < 0.05). CONCLUSIONS: While the primary outcome was not significantly improved, COPD patients demonstrate significant improvements of secondary outcomes (muscle strength and other training-refractory outcomes), suggesting a potential "add-on" effect of the nutritional antioxidant supplementation (vitamins C and E, zinc, and selenium) during PR. This trial is registered with NCT01942889.

HIV is associated with airway obstruction: a matched controlled study.

OBJECTIVE: To explore whether airway obstruction is associated with HIV in a cohort of HIV-infected and uninfected smokers. METHODS: People living with HIV (PLWHIV) participated in the ANRS EP48 HIV CHEST study, an early lung cancer diagnosis study with low-dose chest tomography. HIV-uninfected study participants were from the CONSTANCES cohort. Inclusion criteria were an age greater than 40 years, a smoking history of at least 20 pack-years, and for PLWHIV, a CD4 T-lymphocyte nadir less than 350/µl and last CD4 cell count more than 100 cells/µl. Two randomly selected HIV-uninfected study participants were matched by age and sex with one PLWHIV. Prebronchodilatator forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio was the primary outcome, and association of FEV1/FVC ratio less than 0.70 and FEV1 less than 80% of the theoretical value, as a proxy of chronic obstructive pulmonary disease, the secondary outcome. RESULTS: In total, 351 PLWHIV and 702 HIV-uninfected study participants were included. Median age was 50 years, and 17% of study participants were women. Plasma HIV RNA was less than 50 copies/ml in 89% of PLWHIV, with a median CD4 cell count of 573 cells/µl. HIV (ß -2.19), age (per 10 years increase; ß -2.81), tobacco use (per 5 pack-years increase; ß -0.34), and hepatitis C virus serology (ß-2.50) were negatively associated with FEV1/FVC. HIV [odds ratio (OR: 1.72)], age (per 10 years increase; OR 1.77), and tobacco use (per 5 pack-years increase; OR 1.11) were significantly associated with the secondary outcome. CONCLUSION: Our study found a significant association of airway obstruction with HIV status in smokers aged more than 40 years with previous immunodeficiency.

Impaired training-induced adaptation of blood pressure in COPD patients: implication of the muscle capillary bed.

BACKGROUND AND AIMS: Targeting the early mechanisms in exercise-induced arterial hypertension (which precedes resting arterial hypertension in its natural history) may improve cardiovascular morbidity and mortality in COPD patients. Capillary rarefaction, an early event in COPD before vascular remodeling, is a potential mechanism of exercise-induced and resting arterial hypertension. Impaired training-induced capillarization was observed earlier in COPD patients; thus, this study compares the changes in blood pressure (BP) during exercise in COPD patients and matches control subjects (CSs) after a similar exercise training program, in relationship with muscle capillarization. METHODS: Resting and maximal exercise diastolic pressure (DP) and systolic pressure (SP) were recorded during a standardized cardiopulmonary exercise test, and a quadriceps muscle biopsy was performed before and after training. RESULTS: A total of 35 CSs and 49 COPD patients (forced expiratory volume in 1 second =54%±22% predicted) completed a 6-week rehabilitation program and improved their symptom-limited maximal oxygen uptake (VO2SL: 25.8±6.1 mL/kg per minute vs 27.9 mL/kg per minute and 17.0±4.7 mL/kg per minute vs 18.3 mL/kg per minute; both P<0.001). The improvement in muscle capillary-to-fiber (C/F) ratio was significantly greater in CSs vs COPD patients (+11%±9% vs +23%±21%; P<0.05). Although maximal exercise BP was reduced in CSs (DP: 89±10 mmHg vs 85±9 mmHg; P<0.001/SP: 204±25 mmHg vs 196±27 mmHg; P<0.05), it did not change in COPD patients (DP: 94±14 mmHg vs 97±16 mmHg; P=0.46/SP: 202±27 mmHg vs 208±24 mmHg; P=0.13). The change in muscle C/F ratio was negatively correlated with maximal exercise SP in CSs and COPD patients (r=-0.41; P=0.02). CONCLUSION: COPD patients showed impaired training-induced BP adaptation related to a change in muscle capillarization, suggesting the possibility of blunted angiogenesis.

Involvement of the FoxO1/MuRF1/Atrogin-1 Signaling Pathway in the Oxidative Stress-Induced Atrophy of Cultured Chronic Obstructive Pulmonary Disease Myotubes.

Oxidative stress is thought to be one of the most important mechanisms implicated in the muscle wasting of chronic obstructive pulmonary disease (COPD) patients, but its role has never been demonstrated. We therefore assessed the effects of both pro-oxidant and antioxidant treatments on the oxidative stress levels and atrophic signaling pathway of cultured COPD myotubes. Treatment of cultured COPD myotubes with the pro-oxidant molecule H2O2 resulted in increased ROS production (P = 0.002) and protein carbonylation (P = 0.050), in association with a more pronounced atrophy of the myotubes, as reflected by a reduced diameter (P = 0.003), and the activated expression of atrophic markers MuRF1 and FoxO1 (P = 0.022 and P = 0.030, respectively). Conversely, the antioxidant molecule ascorbic acid induced a reduction in ROS production (P<0.001) and protein carbonylation (P = 0.019), and an increase in the myotube diameter (P<0.001) to a level similar to the diameter of healthy subject myotubes, in association with decreased expression levels of MuRF1, atrogin-1 and FoxO1 (P<0.001, P = 0.002 and P = 0.042, respectively). A significant negative correlation was observed between the variations in myotube diameter and the variations in the expression of MuRF1 after antioxidant treatment (P = 0.047). Moreover, ascorbic acid was able to prevent the H2O2-induced atrophy of COPD myotubes. Last, the proteasome inhibitor MG132 restored the basal atrophy level of the COPD myotubes and also suppressed the H2O2-induced myotube atrophy. These findings demonstrate for the first time the involvement of oxidative stress in the atrophy of COPD peripheral muscle cells in vitro, via the FoxO1/MuRF1/atrogin-1 signaling pathway of the ubiquitin/proteasome system.

Heterogeneity of Systemic Oxidative Stress Profiles in COPD: A Potential Role of Gender.

Oxidative stress (OS) plays a key role in the muscle impairment and exercise capacity of COPD patients. However, the literature reveals that systemic OS markers show great heterogeneity, which may hinder the prescription of effective antioxidant supplementation. This study therefore aimed to identify OS markers imbalance of COPD patients, relative to validated normal reference values, and to investigate the possibility of systemic OS profiles. We measured systemic enzymatic/nonenzymatic antioxidant and lipid peroxidation (LP) levels in 54 stable COPD patients referred for a rehabilitation program. The main systemic antioxidant deficits in these patients concerned vitamins and trace elements. Fully 89% of the COPD patients showed a systemic antioxidant imbalance which may have caused the elevated systemic LP levels in 69% of them. Interestingly, two patient profiles (clusters 3 and 4) had a more elevated increase in LP combined with increased copper and/or decreased vitamin C, GSH, and GPx. Further analysis revealed that the systemic LP level was higher in COPD women and associated with exercise capacity. Our present data therefore support future supplementations with antioxidant vitamins and trace elements to improve exercise capacity, but COPD patients will probably show different positive responses.

Effect of Weight Loss on Postural Changes in Pulmonary Function in Obese Subjects: A Longitudinal Study.

BACKGROUND: Postural changes are known to affect normal lung volumes. A reduction in sitting to supine functional residual capacity (FRC) is well-described in non-obese subjects adopting a supine position. However, postural changes in lung volumes in the obese require further exploration. We aimed to longitudinally address the effects of weight loss on postural changes in lung volumes and pulmonary function in obese subjects. We tested the hypothesis that supine reduction in FRC would be absent in morbid obesity and recovered upon weight loss. METHODS: This was a prospective, observational, longitudinal study. Consecutive morbidly obese adults (N = 12, age: 44 ± 14 y, body mass index: 45 ± 5 kg/m(2)) enrolled in a bariatric surgery program were included. Standard pulmonary function tests and blood gas analysis were performed both before and 1 y after surgery. Pulmonary function was assessed in both the sitting and supine position using spirometry and multi-breath helium dilution. Parameters recorded before and after weight loss were compared. The main outcome measure was FRC. RESULTS: Ten subjects were retested 1 y after surgery (body mass index: 31 ± 5 kg/m(2)). FRC was not affected by change in posture before surgery. Supine reduction in FRC was observed after weight loss (ΔFRC: -0.6 ± 0.4 L, sitting vs supine, P = .002). Pulmonary gas exchange improved (alveolar-to-arterial oxygen partial pressure difference: -8 ± 11 mm Hg, P = .035). CONCLUSIONS: Although postural change in FRC is absent when the morbidly obese adopt a supine position, supine reduction in FRC can be recovered following gastroplasty-induced weight loss, despite residual mild to moderate obesity. This also shows that mild to moderate obesity may affect supine FRC more than morbid obesity. (ClinicalTrials.gov registration NCT02207192.).

Systems medicine approaches for the definition of complex phenotypes in chronic diseases and ageing. From concept to implementation and policies.

Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health) represent the predominant health problem of the Century. The prevention and control of NCDs are the priority of the World Health Organization 2008 Action Plan, the United Nations 2010 Resolution and the European Union 2010 Council. The novel trend for the management of NCDs is evolving towards integrative, holistic approaches. NCDs are intertwined with ageing. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has prioritised NCDs. To tackle them in their totality in order to reduce their burden and societal impact, it is proposed that NCDs should be considered as a single expression of disease with different risk factors and entities. An innovative integrated health system built around systems medicine and strategic partnerships is proposed to combat NCDs. It includes (i) understanding the social, economic, environmental, genetic determinants, as well as the molecular and cellular mechanisms underlying NCDs; (ii) primary care and practice-based interprofessional collaboration; (iii) carefully phenotyped patients; (iv) development of unbiased and accurate biomarkers for comorbidities, severity and follow up of patients; (v) socio-economic science; (vi) development of guidelines; (vii) training; and (viii) policy decisions. The results could be applicable to all countries and adapted to local needs, economy and health systems. This paper reviews the complexity of NCDs intertwined with ageing. It gives an overview of the problem and proposes two practical examples of systems medicine (MeDALL) applied to allergy and to NCD co-morbidities (MACVIA-LR, Reference Site of the European Innovation Partnership on Active and Healthy Ageing).

Novel perspective: exercise training stimulus triggers the expression of the oncoprotein human double minute-2 in human skeletal muscle.

High expression levels of human double minute-2 (Hdm2) are often associated with increased risk of cancer. Hdm2 is well established as an oncoprotein exerting various tumorigenic effects. Conversely, the physiological functions of Hdm2 in nontumor cells and healthy tissues remain largely unknown. We previously demonstrated that exercise training stimulates expression of murine double minute-2 (Mdm2), the murine analog of Hdm2, in rodent skeletal muscle and Mdm2 was required for exercise-induced muscle angiogenesis. Here we showed that exercise training stimulated the expression of Hdm2 protein in human skeletal muscle from +38% to +81%. This robust physiological response was observed in 60-70% of the subjects tested, in both young and senior populations. Similarly, exercise training stimulated the expression of platelet endothelial cell adhesion molecule-1, an indicator of the level of muscle capillarization. Interestingly, a concomitant decrease in the tumor suppressor forkhead box O-1 (FoxO1) transcription factor levels did not occur with training although Mdm2/Hdm2 is known to inhibit FoxO1 expression in diseased skeletal muscle. This could suggest that Hdm2 has different targets when stimulated in a physiological context and that exercise training could be considered therapeutically in the context of cancer in combination with anti-Hdm2 drug therapies in order to preserve Hdm2 physiological functions in healthy tissues.

Blunted muscle angiogenic training-response in COPD patients versus sedentary controls.

The impaired skeletal muscle of chronic obstructive pulmonary disease (COPD) patients reduces exercise capacity. Similar to the oxidative muscle fibres, the angio-adaptation of muscle to training may be blunted in these patients, as in other chronic conditions. We therefore compared muscle functional responses and angio-adaptations after training in COPD patients and sedentary healthy subjects (SHS). 24 COPD patients (forced expiratory volume in 1 s 45.6 ± 17.5% predicted) and 23 SHS (<150 min · week(-1) of moderate-to-vigorous exercise) completed a 6-week rehabilitation programme based on individualised moderate-intensity endurance training. Histomorphological muscle analysis and measurements of pro-angiogenic vascular endothelial growth factor (VEGF)-A and anti-angiogenic thrombospondin (TSP)-1 were conducted before and after training. COPD patients and SHS showed improved symptom-limited oxygen consumption and muscle endurance, although improvements were lower in COPD patients (+0.96 ± 2.4 versus +2.9 ± 2.6 mL · kg(-1) · min(-1), p<0.05, and +65% versus +108%, p = 0.06, respectively). The capillary-to-fibre (C/F) ratio increased less in COPD patients than SHS (+16 ± 10% versus +37 ± 20%, p<0.05) and no fibre type switch occurred in COPD patients. The VEGF-A/TSP-1 ratio increased in COPD patients and SHS (+65% versus +35%, p<0.05). Changes in C/F and symptom-limited oxygen consumption were correlated (r = 0.51, p<0.05). In addition to a lack of fibre switch, COPD patients displayed a blunted angiogenic response to training.

Evidence of an early physical activity reduction in chronic obstructive pulmonary disease patients.

OBJECTIVE: To compare the lifetime pattern of physical activity (PA) in chronic obstructive pulmonary disease (COPD) patients and sedentary healthy subjects (SHS) using a PA questionnaire with a lifetime period of recall (Quantification de l'Activité Physique [QUANTAP] system), and to compare the pattern of PA reduction in COPD patients with the onset of breathlessness and other relevant clinical events in this disease (diagnosis, first rehabilitation, onset of smoking). DESIGN: Cross-sectional comparative study. SETTINGS: Outpatient university hospital and inpatient pulmonary rehabilitation center. PARTICIPANTS: COPD patients (n=129; mean age ± SD, 61±10y; forced expiratory volume in 1s, 57±23%) and SHS (n=29; mean age ± SD, 61±5y; <150min·wk(-1) of moderate-vigorous PA). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Lifetime PA was compared in COPD patients and SHS using the QUANTAP system. The patients with COPD and SHS underwent pulmonary function, exercise, and quadriceps endurance testing. The current PA level was assessed with a triaxial accelerometer and the Voorrips questionnaire. The age at the onset of breathlessness was also recorded. RESULTS: Accelerometry showed no significant difference between patients and SHS (in vector magnitude units, 136±56 vs 135±47; P=.95). Within the past 15 years, the cumulated PA level was not different for each 5-year period. Then, from the period of 16 to 40 years ago, it was systematically higher in patients compared with SHS (in metabolic equivalent/y(-1); median [interquartile range], 6973 [5400-12,207] vs 4248 [3545-5919]; P<.05). The COPD patients reduced their PA earlier than the SHS (45y vs 55y; P<.01), and the PA was dropped before the onset of breathlessness (45y vs 49y; P<.001). CONCLUSIONS: The observation of an early PA reduction, preceding the onset of breathlessness, suggests the implication of prior pathologic mechanisms in the PA reduction of COPD patients.

Age-dependent bupivacaine-induced muscle toxicity during continuous peripheral nerve block in rats.

BACKGROUND: Regional blocks improve postoperative analgesia and postoperative rehabilitation in children and adult patients. Continuous peripheral nerve blocks have been proposed as safe and effective techniques for postoperative pain relief and chronic pain therapy, particularly in small children. Few clinical reports have described myotoxicity induced by bupivacaine in these young patients, in contrast with a larger number of observations in adults. Here, the authors addressed this issue by a comparative evaluation of bupivacaine-induced myotoxicity in young versus adult rats. METHODS: Femoral nerve block catheters were inserted in male Wistar rats. Young (3-week-old) and adult (12-week-old) rats were randomly assigned to received seven injections (1 ml/kg) of 0.25% bupivacaine (n = 6 per experiment) or isotonic saline (n = 6 per experiment) at 8-h intervals. Rats were killed 8 h after the last injection. Psoas muscle adjacent to the femoral nerve was quickly dissected. Oxygen consumption rates were measured in saponin-skinned fibers, mitochondrial adenosine triphosphate synthesis rates were determined by bioluminescence, and citrate synthase activity was determined by spectrophotometry. Muscle ultrastructural damage was also examined and scored as normal, focal disruption, moderate disruption, or extreme disruption of the sarcomeres. RESULTS: Bupivacaine caused a reduction of mitochondrial adenosine triphosphate synthesis rate, a decrease of citrate synthase activity, and muscle ultrastructural damages. Young rats treated with bupivacaine showed more severe alterations of mitochondrial bioenergetics and muscle ultrastructure. CONCLUSIONS: These findings demonstrate that bupivacaine-induced myotoxicity can be explained by mitochondrial bioenergetics alterations, which are more severe in young rats.

Implication of xanthine oxidase in muscle oxidative stress in COPD patients.

OBJECTIVE: The aim of this study was to determine the implication of xanthine oxidase (XO) in the exercise-induced muscle oxidative stress and muscle dysfunction of these patients. METHODS: A randomized, crossover and double-blind study was conducted in nine severe COPD patients, who performed a localized quadriceps endurance test after oral treatment with allopurinol, a XO inhibitor or placebo. Redox status was studied in arterial and venous femoral blood before and after the endurance test. RESULTS: In placebo condition, muscle exercise resulted in a significant increase in AOPP and isoprostanes, with a significant increase in the venoarterial difference (v-a) in isoprostanes after exercise as compared with before (p<0.05). In contrast, allopurinol treatment prevented the elevation in AOPP levels and v-a isoprostanes after exercise. However, no significant improvement in quadriceps muscle endurance was observed, but allopurinol treatment seemed to preserve muscle strength properties. CONCLUSION: This study demonstrates that XO is implicated in the exercise-induced muscle oxidative stress of COPD patients. Allopurinol administration seemed to improve only some muscle properties. Therefore other sources of muscle oxidative stress should be implicated in muscle dysfunction observed in these patients.