RESUMEN
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.
Asunto(s)
Carnosina , Enfermedad Pulmonar Obstructiva Crónica , Anciano , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Carnosina/farmacología , Carnosina/uso terapéutico , Suplementos Dietéticos , Ejercicio Físico/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , beta-Alanina/farmacología , beta-Alanina/uso terapéuticoRESUMEN
Among the comorbidities associated with chronic obstructive pulmonary disease (COPD), skeletal muscle weakness and atrophy are known to affect patient survival rate. In addition to muscle deconditioning, various systemic and intrinsic factors have been implicated in COPD muscle dysfunction but an impaired COPD muscle adaptation to contraction has never been extensively studied. We submitted cultured myotubes from nine healthy subjects and nine patients with COPD to an endurance-type protocol of electrical pulse stimulation (EPS). EPS induced a decrease in the diameter, covered surface and expression of MHC1 in COPD myotubes. Although the expression of protein degradation markers was not affected, expression of the protein synthesis marker mTOR was not induced in COPD compared to healthy myotubes after EPS. The expression of the differentiation markers p16INK4a and p21 was impaired, while expression of Myf5 and MyoD tended to be affected in COPD muscle cells in response to EPS. The expression of mitochondrial biogenesis markers PGC1α and MFN2 was affected and expression of TFAM and COX1 tended to be reduced in COPD compared to healthy myotubes upon EPS. Lipid peroxidation was increased and the expression of the antioxidant enzymes SOD2 and GPx4 was affected in COPD compared to healthy myotubes in response to EPS. Thus, we provide evidence of an impaired response of COPD muscle cells to contraction, which might be involved in the muscle weakness observed in patients with COPD.
Asunto(s)
Terapia por Estimulación Eléctrica , Células Musculares/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Estudios de Casos y Controles , Diferenciación Celular , Femenino , Humanos , Peroxidación de Lípido , Masculino , Persona de Mediana Edad , Fibras Musculares Esqueléticas/patología , Biogénesis de Organelos , Estrés Oxidativo , ProteolisisRESUMEN
INTRODUCTION: Exercise intolerance is common in patients with chronic obstructive pulmonary disease (COPD) and, although multifactorial, it is largely caused by lower-limb muscle dysfunction. Research has shown that patients with severe to very severe COPD have significantly lower levels of muscle carnosine, which acts as a pH buffer and antioxidant. Beta-alanine (BA) supplementation has been shown to consistently elevate muscle carnosine in a variety of populations and may therefore improve exercise tolerance and lower-limb muscle function. The primary objective of the current studies is to assess the beneficial effects of BA supplementation in enhancing exercise tolerance on top of two types of exercise training (non-linear periodised exercise (NLPE) training or neuromuscular electrical stimulation (NMES)) in patients with COPD. METHODS AND ANALYSIS: Two randomised, double-blind, placebo-controlled trials have been designed. Patients will routinely receive either NLPE (BASE-TRAIN trial) or NMES (BASE-ELECTRIC trial) as part of standard exercise-based care during their 8-to-10 week pulmonary rehabilitation (PR) programme. A total of 222 patients with COPD (2×77 = 154 patients in the BASE-TRAIN trial and 2×34 = 68 patients in the BASE-ELECTRIC trial) will be recruited from two specialised PR centres in The Netherlands. For study purposes, patients will receive 3.2 g of oral BA supplementation or placebo per day. Exercise tolerance is the primary outcome, which will be assessed using the endurance shuttle walk test (BASE-TRAIN) or the constant work rate cycle test (BASE-ELECTRIC). Furthermore, quadriceps muscle strength and endurance, cognitive function, carnosine levels (in muscle), BA levels (in blood and muscle), markers of oxidative stress and inflammation (in blood, muscles and lungs), physical activity and quality of life will be measured. ETHICS AND DISSEMINATION: Both trials were approved by CMO Regio Arnhem-Nijmegen, The Netherlands (NL70781.091.19. and NL68757.091.19). TRIAL REGISTRATION NUMBER: NTR8427 (BASE-TRAIN) and NTR8419 (BASE-ELECTRIC).
Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica , Calidad de Vida , Suplementos Dietéticos , Método Doble Ciego , Estimulación Eléctrica , Ejercicio Físico , Terapia por Ejercicio , Tolerancia al Ejercicio , Humanos , Países Bajos , Enfermedad Pulmonar Obstructiva Crónica/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , beta-AlaninaRESUMEN
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.
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Suplementos Dietéticos/análisis , Pulmón/fisiopatología , Músculo Esquelético/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Estrés Oxidativo , Enfermedad Pulmonar Obstructiva Crónica/patología , Anciano , Ácido Ascórbico/sangre , Biomarcadores/sangre , Cobre/sangre , Ejercicio Físico , Femenino , Glutatión/sangre , Glutatión Peroxidasa/sangre , Humanos , Peroxidación de Lípido , Masculino , Persona de Mediana Edad , Análisis de Componente Principal , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Factores SexualesRESUMEN
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease characterized by progressive weakness and atrophy of specific skeletal muscles. As growing evidence suggests that oxidative stress may contribute to FSHD pathology, antioxidants that might modulate or delay oxidative insults could help in maintaining FSHD muscle function. Our primary objective was to test whether oral administration of vitamin C, vitamin E, zinc gluconate, and selenomethionine could improve the physical performance of patients with FSHD. Adult patients with FSHD (n=53) were enrolled at Montpellier University Hospital (France) in a randomized, double-blind, placebo-controlled pilot clinical trial. Patients were randomly assigned to receive 500 mg vitamin C, 400mg vitamin E, 25mg zinc gluconate and 200 µg selenomethionine (n=26), or matching placebo (n=27) once a day for 17 weeks. Primary outcomes were changes in the two-minute walking test (2-MWT), maximal voluntary contraction, and endurance limit time of the dominant and nondominant quadriceps (MVCQD, MVCQND, TlimQD, and TlimQND, respectively) after 17 weeks of treatment. Secondary outcomes were changes in the antioxidant status and oxidative stress markers. Although 2-MWT, MVCQ, and TlimQ were all significantly improved in the supplemented group at the end of the treatment compared to baseline, only MVCQ and TlimQ variations were significantly different between groups (MVCQD: P=0.011; MVCQND: P=0.004; TlimQD: P=0.028; TlimQND: P=0.011). Similarly, the vitamin C (P<0.001), vitamin E as α-tocopherol (P<0.001), vitamin C/vitamin E ratio (P=0.017), vitamin E γ/α ratio (P=0.022) and lipid peroxides (P<0.001) variations were significantly different between groups. In conclusion, vitamin E, vitamin C, zinc, and selenium supplementation has no significant effect on the 2-MWT, but improves MVCQ and TlimQ of both quadriceps by enhancing the antioxidant defenses and reducing oxidative stress. This trial was registered at clinicaltrials.gov (number: NCT01596803).
Asunto(s)
Ácido Ascórbico/administración & dosificación , Suplementos Dietéticos , Gluconatos/administración & dosificación , Músculo Esquelético/efectos de los fármacos , Distrofia Muscular Facioescapulohumeral/dietoterapia , Selenometionina/administración & dosificación , Vitamina E/administración & dosificación , Administración Oral , Adulto , Método Doble Ciego , Femenino , Marcha/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Distrofia Muscular Facioescapulohumeral/metabolismo , Distrofia Muscular Facioescapulohumeral/fisiopatología , Estrés Oxidativo , Resistencia Física/efectos de los fármacos , Proyectos Piloto , CaminataRESUMEN
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).
Asunto(s)
Envejecimiento/patología , Prestación Integrada de Atención de Salud/métodos , Fenotipo , Envejecimiento/fisiología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/terapia , Enfermedad Crónica , Comorbilidad , Prestación Integrada de Atención de Salud/tendencias , Política de Salud/tendencias , Humanos , Neoplasias/epidemiología , Neoplasias/terapiaRESUMEN
BACKGROUND: In chronic respiratory failure (CRF), body composition strongly predicts survival. METHODS: A prospective randomised controlled trial was undertaken in malnourished patients with CRF to evaluate the effects of 3 months of home rehabilitation on body functioning and composition. 122 patients with CRF on long-term oxygen therapy and/or non-invasive ventilation (mean (SD) age 66 (10) years, 91 men) were included from eight respiratory units; 62 were assigned to home health education (controls) and 60 to multimodal nutritional rehabilitation combining health education, oral nutritional supplements, exercise and oral testosterone for 90 days. The primary endpoint was exercise tolerance assessed by the 6-min walking test (6MWT). Secondary endpoints were body composition, quality of life after 3 months and 15-month survival. RESULTS: Mean (SD) baseline arterial oxygen tension was 7.7 (1.2) kPa, forced expiratory volume in 1 s 31 (13)% predicted, body mass index (BMI) 21.5 (3.9) kg/m2 and fat-free mass index (FFMI) 15.5 (2.4) kg/m2. The intervention had no significant effect on 6MWT. Improvements (treatment effect) were seen in BMI (+0.56 kg/m2, 95% CI 0.18 to 0.95, p=0.004), FFMI (+0.60 kg/m2, 95% CI 0.15 to 1.05, p=0.01), haemoglobin (+9.1 g/l, 95% CI 2.5 to 15.7, p=0.008), peak workload (+7.2 W, 95% CI 3.7 to 10.6, p<0.001), quadriceps isometric force (+28.3 N, 95% CI 7.2 to 49.3, p=0.009), endurance time (+5.9 min, 95% CI 3.1 to 8.8, p<0.001) and, in women, Chronic Respiratory Questionnaire (+16.5 units, 95% CI 5.3 to 27.7, p=0.006). In a multivariate Cox analysis, only rehabilitation in a per-protocol analysis predicted survival (HR 0.27, 95% CI 0.07 to 0.95, p=0.042). CONCLUSIONS: Multimodal nutritional rehabilitation aimed at improving body composition increased exercise tolerance, quality of life in women and survival in compliant patients, supporting its incorporation in the treatment of malnourished patients with CRF. Clinical Trial number NCT00230984.