- Email: [email protected]
Nutrition as a Metabolic Modulator in COPD
CHEST
Translating Basic Research Into Clinical Practice
Nutrition as a Metabolic Modulator in COPD Annemie M. W. J. Schols, PhD
COPD is an important global health problem. In addition to pulmonary impairment, systemic inflammation, musculoskeletal abnormalities, and cardiovascular comorbidity influence disease burden and mortality risk. Body weight and body composition are important discriminants in classifying disease heterogeneity. The rationale for and efficacy of caloric supplementation in preventing and treating involuntary weight loss is currently well established. For maintenance of muscle and bone tissue, appropriately timed, high-quality protein intake and addressing vitamin D deficiency must be considered. Specific nutrients (eg, n-3 polyunsaturated fatty acids and polyphenolic compounds) may have the pharmacologic potential to boost decreased muscle mitochondrial metabolism and enhance impaired physical performance, particularly when the metabolic stimulus of physical activity alone is limited. At this stage, evidence is insufficient to support an intake of high doses of single nutritional supplements to modulate respiratory pathology, but some small studies have identified micronutrient modulation via the diet as a promising intervention. CHEST 2013; 144(4):1340–1345 Abbreviations: AA 5 amino acid; BCAA 5 branched-chain amino acid; CH 5 carbohydrate; mTOR 5 mammalian target of rapamycin; NF-kB 5 nuclear factor kappa B; PGC-1a 5 peroxisome proliferator-activated receptor coactivator 1a; PPAR 5 peroxisome proliferator-activated receptor; RCT 5 randomized clinical trial; SIRT 5 sirtuin; SPE 5 splanchnic extraction; TNF 5 tumor necrosis factor
is an important global health problem. The COPD lung disorder is characterized by progressive airflow
obstruction resulting from inflammation and remodeling of the airways, and may include development of emphysema. Furthermore, systemic disease manifestations and frequent acute exacerbations influence the disease burden and mortality risk.1 Two recent unbiased statistical approaches to classifying COPD heterogeneity identified body weight as a discriminant2,3 for emphysema, musculoskeletal abnormalities, and cardiovascular comorbidity. Although initially considered as inevitable and a terminal progression of the disease process, there is now convincing evidence that weight loss is not an adaptive mechanism to decrease the metabolic rate in COPD. Conversely, the 2012 Cochrane meta-analysis shows that oral nutritional supplementation improves nutritional status in malnourished patients with COPD without compromising the ventilatory system, and even improves respiratory muscle strength and healthrelated quality of life.4 The incorporation of body composition into nutritional assessment has been a major step forward in understanding systemic COPD pathophysiology and nutritional potential. An impor-
tant role for muscle atrophy and a decreased muscle oxidative metabolism on impaired physical performance have been demonstrated, providing new leads in nutritional supplementation that enhance exercise performance in COPD, not only confined to advanced disease but also in earlier stages.5 In addition, a pivotal role for visceral adiposity and poor dietary quality in COPD risk and progression emerges,6 which positions nutritional intervention as an integral part of disease management, from prevention to chronic respiratory failure (Fig 1). Involuntary Weight Loss and Energy Balance Regulation Weight loss occurs when energy expenditure exceeds energy intake; it may occur gradually or stepwise. In the acute phase of respiratory exacerbations, loss of appetite and diminished dietary intake are often experienced in concert with elevated systemic levels of the appetite-regulating hormone leptin and proinflammatory cytokines.7 However, anorexia is not the primary trigger of a disturbed energy balance in clinically stable disease, because a normal to increased dietary
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intake is reported in underweight patients.8 Moreover, although the normal response to semistarvation is a reduced metabolic rate and depressed whole-body protein turnover, weight-losing patients with COPD often display an elevated resting energy expenditure9 and increased whole-body protein turnover.10,11 In many other chronic inflammatory diseases and cancer, increased resting energy expenditure is associated with a decreased physical activity-induced thermogenesis. In contrast, decreased efficiency of lower-limb muscle contraction12 and decreased ventilatory efficiency contribute to elevated daily energy requirements in COPD. The latter was elegantly illustrated by the association of weight gain with improved lung function and ventilatory efficiency after lung reduction surgery.13 Collectively, this indicates a hypermetabolic state that may contribute to weight loss if energy requirements are not fully met and provides convincing evidence for caloric supplementation to maintain or increase body weight. Early concerns about adverse effects of carbohydrate (CH) supplementation in COPD due to increased CO2 production resulting from CH oxidation loading ventilation have not been substantiated in more recent studies but were observed only after hyperalimentation14; this can easily be avoided by smaller meal portions spread throughout the day. Moreover, from the perspective of enhancing physical performance, there is a strong rationale for prioritizing CH oxidation during exercise training in COPD. Structural and metabolic abnormalities in the skeletal muscles of patients with COPD include reductions in the proportion of type 1 fibers and mitochondrial density, resulting in decreased fat oxidative capacity and increased glucose production.15,16 The functional consequence is early muscle fatigue associated with early lactic acid rise and adenine nucleotide loss, even at the low absolute exercise intensities patients with COPD can achieve. Adequately timed oral nutritional supplements with a higher CH and lower fat composition may be beneficial because digestible CHs are a rapid energy source in the muscle without leading to satiety precluding normal food intake. This is especially relevant for patients with COPD who experience poor appetite because of postprandial shortness Manuscript received February 12, 2013; revision accepted April 1, 2013. Affiliations: From the Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands. Correspondence to: Annemie M. W. J. Schols, PhD, Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0326
Figure 1. COPD from an integrative metabolic perspective.
of breath, because CH-rich supplements induce less shortness of breath than do fat-rich supplements.14 Proof of concept was further provided in a randomized clinical trial (RCT) showing a correlation between increasing CH intake and improved exercise performance after low-intensity aerobic exercise in COPD.17 Nutritional Potential of Boosting Mitochondrial Function High-intensity aerobic exercise improves insulin sensitivity, induces mitochondrial biogenesis in skeletal muscle, and induces loss of visceral fat mass. Not only obese but also normal-weight patients with COPD are at increased risk of these disturbances in metabolic health because of decreased muscle oxidative capacity combined with selectively increased abdominal visceral fat mass.6 However, the efficacy of aerobic exercise may be limited by ventilatory impairment in COPD. Alternatively, or as an adjunct to exercise, the muscle oxidative metabolism may be stimulated nutritionally. Peroxisome proliferator-activated receptors (PPARs) a and d and their coactivator PPAR coactivator 1a (PGC-1a), together with mitochondrial transcription factor-A, promote mitochondrial biogenesis and a slow fiber-type muscle phenotype.18 The protein and mRNA levels of these constituents were decreased in COPD quadriceps muscle.19 Moreover, in vitro research revealed that tumor necrosis factor (TNF)-a, by activation of nuclear factor kappa B (NF-kB), induces a shift in muscle fiber composition toward a fast glycolytic (type 2) isoform and impairs muscle oxidative metabolism by inhibiting the PGC-1a/PPAR signaling pathway.19 Additionally, patients with COPD and elevated levels of muscle TNF-a displayed decreased expression
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of oxidative genes and impaired PGC-1a/PPAR expression compared with patients with COPD and normal muscle TNF-a levels.19 Polyunsaturated fatty acids present in, for example, oils, seafood, and walnuts, are the natural ligands of PPARs, and an RCT showed that polyunsaturated fatty acid supplementation as an adjunct to exercise training indeed significantly enhanced improvement in endurance exercise capacity in COPD.20 This may imply a stimulating effect on muscle fat oxidative metabolism by inhibiting classic NF-kB signaling or stimulating PGC-1a/PPAR signaling. Resveratrol, a natural polyphenolic compound, present in small amounts in the human diet (eg, in mulberries, peanuts, grapes, and red wines), has also been put forward as potential nutraceutical to boost mitochondria. Resveratrol is suggested to impact on the metabolic regulator AMP-activated kinase, which, in turn, affects NAD1 levels, resulting in activation of sirtuin (SIRT) 1, a member of the protein family of NAD1-dependent deacetylases, and activation of PGC1a.21 It was shown in COPD that phospho-AMP-activated kinase levels were lower in patients with a type 1oII fiber shift and correlated with quadriceps endurance.22 Alternatively, cellular NAD1 (re)synthesis may be stimulated directly. Recently, nicotinamide riboside, present in low doses in milk, was found to boost both cellular and mitochondrial NAD1 levels, leading, via different pathways, to synergistic activation of both nuclear SIRT1 and mitochondrial SIRT3.23 Decreased SIRT3 expression has been reported in COPD muscle, which positively correlated with peak oxygen consumption.24 RCTs are needed to investigate the effect of nutraceuticals on mitochondrial function in COPD. The response may be different between peripheral skeletal muscle and the diaphragm, because the diaphragm in COPD is adapted toward an increased oxidative phenotype.25 Nutritional Modulation of Muscle Protein Turnover Generalized atrophy of muscle mass is an inevitable consequence of weight loss, but lower-limb muscle atrophy is also prevalent in normal, stable-weight patients with COPD and is an independent predictor of survival.26 Muscle mass is determined by the net balance of muscle protein synthesis and protein breakdown. Increased whole-body protein turnover has been demonstrated consistently in COPD,10,11 but no recent data exist on the muscle protein synthesis rate, and there is only indirect evidence of an increased muscle protein degradation rate in muscle-wasted patients.27 Analyses of the effector pathways of protein degradation have so far focused on components of the ubiquitin 26S-proteasome system (eg, the E3 ubiquitin-ligase
atrogin-1, polyubiquitinated protein levels), which were found to be consistently elevated.18 Conversely, protein synthesis signaling cues (insulin-like growth factor 1 and phospho-Akt expression levels) are mainly unaltered or, in one study, even increased.18 Nutritional intervention should, therefore, be targeted at the provision of sufficient amino acids (AAs) to support the potentially elevated protein synthesis signaling as a compensatory response to the apparent increases in proteolysis cues. Stimulation of protein synthesis depends on the availability of AAs in the blood stream. Patients with COPD and muscle atrophy have low plasma levels of branched-chain AAs (BCAAs) compared with age-matched control subjects.28 It is well known that BCAAs, in particular leucine, are able to stimulate the anabolic mammalian target of rapamycin (mTOR) signaling cascade and protein synthesis. Recently, it was elegantly shown in vitro that leucine supplementation stimulates myofibrillar protein rather than generic protein accretion in skeletal muscle, and that this involves pretranslational control of myosin heavy chain expression of leucine in an mTORindependent and mTOR-dependent manner.29 As dietary protein is digested and absorbed by the gut, first-pass splanchnic extraction (SPE) of AAs plays a key role in modifying the capacity for protein anabolism during feeding. Several studies have consistently reported an increased first-pass SPE of the AAs leucine and phenylalanine in the elderly, limiting the flow and availability of dietary AA to peripheral tissues. In contrast, a strikingly lower SPE was found in patients with COPD, associated with an enhanced anabolic response to a protein meal, suggesting that the metabolic efficiency of feeding was increased in COPD.30 BCAA supplementation also altered the interorgan metabolism in favor of the peripheral (ie, muscle) compartment.31 Further research is required to investigate whether this potential adaptive mechanism fails in patients with COPD and acute muscle wasting and/or emphysema, because the latter exhibited a depressed muscle protein synthesis32 and a blunted whole-body protein turnover after acute exercise.33 Increased levels of oxidative stress in COPD skeletal muscle have been reported consistently.15 Of the signaling pathways sensitive to oxidative stress and involved in muscle mass regulation, quadriceps biopsy analyses have suggested activation of FOXO, mitogenactivated protein kinase, and NF-kB.15 Mitogenactivated protein kinase and NF-kB signaling is also initiated by inflammation, and increased inflammatory cell infiltration and cytokine expression have been reported in some studies.15 These regulatory pathways of proteolysis or their triggers, oxidative stress and inflammation, could, therefore, be considered as therapeutic targets. Although it has been shown experimentally that NF-kB is sensitive to nutritional intervention
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(ie, the polyunsaturated fatty acids EPA and DHA), therapies to attenuate muscle proteolysis will likely require inclusion of a pharmacologic agent targeting additional signaling axes involved in muscle maintenance regulation. However, to truly understand the cause of muscle wasting at a cellular basis and to develop optimal multimodal intervention strategies, studies analyzing the regulatory and effector pathways of muscle protein turnover should not be limited to a cross-sectional comparison of well-phenotyped subpopulations of COPD, but ideally have a longitudinal design.
The other RCT showed good compliance with a dietary shift, but no association between increasing food and vegetable intake and changes in biomarkers of inflammation and oxidative stress after only 12 weeks of intervention.40 Together, the current evidence strongly suggests that a prudent dietary pattern (rich in fresh vegetables, fruit, oily fish, wine, and cereals) may protect against COPD, especially in smokers, and that dietary intervention in the management of COPD should target a healthy pattern.41-43
Conclusions Micronutrient Deficiency and Supplementation Vitamin D has pleiotropic effects in several tissues and cells, many of which are relevant to COPD. Based on international accepted cutoffs, vitamin D deficiency is highly prevalent in COPD and is associated with decreased lung function and muscle function, osteoporosis, and compromised immune function.34 According to international population guidelines, once vitamin D deficiency has been diagnosed, supplementation is recommended because of its beneficial effects on the bone and its proven benefits in fall-related injuries in populations at risk, such as those with COPD. Daily intakes, in addition to a minimal amount of ultraviolet exposure, vary with age, but a dose of 800 International Units with 1 g of calcium is considered to be largely sufficient. The potential of high-dose supplementation to obtain other effects needs further investigation. A meta-analysis in healthy adults showed a positive effect of vitamin D supplementation on muscle strength in patients with plasma 25(OH)D concentrations , 25 nmol/L only.35 More mechanistic insight was provided in this susceptible group from a study demonstrating a positive effect of vitamin D therapy on skeletal muscle mitochondrial oxidative phosphorylation, which is highly relevant for COPD, as discussed previously.36 Evidence of an inverse association between increased dietary fiber intake and respiratory mortality is convincing.37,38 Dietary fiber has been shown to alter gut immunity and to reduce systemic inflammation, which may be mediated by alterations in the gut microbiome. Epidemiologic evidence furthermore supports a positive relationship between fruit and vegetable intake, lung function, and COPD, which may attenuate oxidative stress. So far, two RCTs have investigated the compliance and efficacy of a dietary shift to higher antioxidant food intake in moderate-to-severe COPD. During a 3-year intervention period, a smaller decline in lung function was shown in patients who shifted from a low to a moderate intake of fruit and vegetables.39
Nutrition in COPD has been topic of extensive scientific research since the landmark paper by Wilson et al44 in 1985. The role of caloric supplementation in preventing and treating weight loss is currently well established. High-quality protein intake and repletion of vitamin D deficiency must be considered for the maintenance of muscle and bone tissue. Specific nutrients may have a pharmacologic potential to enhance physical performance, in particular when physical activity as a metabolic stimulus is limited and when muscle mitochondrial function is impaired. At this stage, evidence is insufficient to support an intake of high doses of single supplements to modulate respiratory pathology, but small studies have identified micronutrient modulation through the diet as a promising intervention.
Acknowledgments Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr Schols has participated in speaking activities and international advisory committees for different nutritional and pharmaceutical companies, sometimes receiving an honorarium.
References 1. Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Resp Crit Care Med. 2013;187(4):347-365. 2. Burgel PR, Paillasseur JL, Peene B, et al. Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality. PLoS ONE. 2012;7(12): e51048. 3. Vanfleteren LE, Spruit MA, Groenen M, et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Resp Crit Care Med. 2013;187(7): 728-735. 4. Ferreira IM, Brooks D, White J, Goldstein R. Nutritional supplementation for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;(12):CD000998. 5. van den Borst B, Slot IG, Hellwig VA, et al. Loss of quadriceps muscle oxidative phenotype and decreased endurance in
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patients with mild-to-moderate COPD. J Appl Physiol. 2013; 114(9):1319-1328. van den Borst B, Gosker HR, Schols AM. Central fat and peripheral muscle: partners in crime in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(1): 8-13. Creutzberg EC, Wouters EF, Vanderhoven-Augustin IM, Dentener MA, Schols AM. Disturbances in leptin metabolism are related to energy imbalance during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;162(4 pt 1):1239-1245. Goris AH, Vermeeren MA, Wouters EF, Schols AM, Westerterp KR. Energy balance in depleted ambulatory patients with chronic obstructive pulmonary disease: the effect of physical activity and oral nutritional supplementation. Br J Nutr. 2003; 89(5):725-731. Schols AM, Soeters PB, Mostert R, Saris WH, Wouters EF. Energy balance in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1991;143(6):1248-1252. Kao CC, Hsu JW, Bandi V, Hanania NA, Kheradmand F, Jahoor F. Resting energy expenditure and protein turnover are increased in patients with severe chronic obstructive pulmonary disease. Metabolism. 2011;60(10):1449-1455. Engelen MP, Deutz NE, Wouters EF, Schols AM. Enhanced levels of whole-body protein turnover in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;162(4 pt 1):1488-1492. Layec G, Haseler LJ, Hoff J, Richardson RS. Evidence that a higher ATP cost of muscular contraction contributes to the lower mechanical efficiency associated with COPD: preliminary findings. Am J Physiol Regul Integr Comp Physiol. 2011; 300(5):R1142-1147. Kim V, Kretschman DM, Sternberg AL, et al. Weight gain after lung reduction surgery is related to improved lung function and ventilatory efficiency. Am J Respir Crit Care Med. 2012;186(11):1109-1116. Vermeeren MA, Wouters EF, Nelissen LH, van Lier A, Hofman Z, Schols AM. Acute effects of different nutritional supplements on symptoms and functional capacity in patients with chronic obstructive pulmonary disease. Am J Clin Nutr. 2001;73(2):295-301. Remels AH, Gosker HR, Langen RC, Schols AM. The mechanisms of cachexia underlying muscle dysfunction in COPD. J Appl Physiol. 2013;114(9):1253-1262. Franssen FM, Sauerwein HP, Ackermans MT, Rutten EP, Wouters EF, Schols AM. Increased postabsorptive and exerciseinduced whole-body glucose production in patients with chronic obstructive pulmonary disease. Metabolism. 2011; 60(7):957-964. Steiner MC, Barton RL, Singh SJ, et al. Nutritional enhancement of exercise performance in chronic obstructive pulmonary disease: a randomised controlled trial. Thorax. 2003;58(9): 745-751. Remels AH , Schrauwen P, Broekhuizen R , et al. Peroxisome proliferator-activated receptor expression is reduced in skeletal muscle in COPD. Eur Respir J. 2007;30(2): 245-252. Remels AH, Gosker HR, Schrauwen P, et al. TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia? FASEB J. 2010;24(12):5052-5062. Broekhuizen R, Wouters EF, Creutzberg EC, Weling-Scheepers CA, Schols AM. Polyunsaturated fatty acids improve exercise capacity in chronic obstructive pulmonary disease. Thorax. 2005;60(5):376-382. Park SJ, Ahmad F, Philp A, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 2012;148(3):421-433.
22. Natanek SA, Gosker HR, Slot IG, et al. Pathways associated with reduced quadriceps oxidative fibres and endurance in COPD. Eur Respir J. 2013;41(6):1275-1283. 23. Canto C, Houtkooper RH, Pirinen E, et al. The NAD(1) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15(6):838-847. 24. Turan N, Kalko S, Stincone A, et al. A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease. PLoS Comput Biol. 2011;7(9):e1002129. 25. Caron MA, Debigaré R, Dekhuijzen PN, Maltais F. Comparative assessment of the quadriceps and the diaphragm in patients with COPD. J Appl Physiol. 2009;107(3):952-961. 26. Marquis K, Debigaré R, Lacasse Y, et al. Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166(6):809-813. 27. Rutten EP, Franssen FM, Engelen MP, Wouters EF, Deutz NE, Schols AM. Greater whole-body myofibrillar protein breakdown in cachectic patients with chronic obstructive pulmonary disease. Am J Clin Nutr. 2006;83(4):829-834. 28. Engelen MP, Wouters EF, Deutz NE, Menheere PP, Schols AM. Factors contributing to alterations in skeletal muscle and plasma amino acid profiles in patients with chronic obstructive pulmonary disease. Am J Clin Nutr. 2000;72(6):1480-1487. 29. Haegens A, Schols AM, van Essen AL, van Loon LJ, Langen RC. Leucine induces myofibrillar protein accretion in cultured skeletal muscle through mTOR dependent and -independent control of myosin heavy chain mRNA levels. Mol Nutr Food Res. 2012;56(5):741-752. 30. Engelen MP, De Castro CL, Rutten EP, Wouters EF, Schols AM, Deutz NE. Enhanced anabolic response to milk protein sip feeding in elderly subjects with COPD is associated with a reduced splanchnic extraction of multiple amino acids. Clin Nutr. 2012;31(5):616-624. 31. Engelen MP, Rutten EP, De Castro CL, Wouters EF, Schols AM, Deutz NE. Supplementation of soy protein with branchedchain amino acids alters protein metabolism in healthy elderly and even more in patients with chronic obstructive pulmonary disease. Am J Clin Nutr. 2007;85(2):431-439. 32. Morrison WL, Gibson JN, Scrimgeour C, et al. Muscle wasting in emphysema. Clin Sci Lond. 1988;75(4):415-420. 33. Engelen MP, Deutz NE, Mostert R, Wouters EF, Schols AM. Response of whole-body protein and urea turnover to exercise differs between patients with chronic obstructive pulmonary disease with and without emphysema. Am J Clin Nutr. 2003;77(4):868-874. 34. Janssens W, Lehouck A, Carremans C, et al. Vitamin D beyond bones in chronic obstructive pulmonary disease: time to act. Am J Respir Crit Care Med. 2009;179:630-636. 35. Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL. Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int. 2011; 22(3):859-871. 36. Sinha A, Hollingsworth KG, Ball S, Cheetham T. Improving the vitamin D status of vitamin D deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle. J Clin Endocrinol Metab. 2013;98(3):E509-E513. 37. Chuang SC, Norat T, Murphy N, et al. Fiber intake and total and cause-specific mortality in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr. 2012;96(1):164-174. 38. Varraso R, Willett WC, Camargo CA, Jr. Prospective study of dietary fiber and risk of chronic obstructive pulmonary disease among US women and men. Am J Epidemiol. 2010;171(7): 776-784.
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39. Keranis E, Makris D, Rodopoulou P, et alImpact of dietary shift to higher-antioxidant foods in COPD: a randomised trial. Eur Respir J. 2010;36(4):774-780. 40. Baldrick FR, Elborn JS, Woodside JV, et al. Effect of fruit and vegetable intake on oxidative stress and inflammation in COPD: a randomised controlled trial. Eur Respir J. 2012; 39(6):1377-1384. 41. Varraso R, Fung TT, Hu FB, Willett W, Camargo CA. Prospective study of dietary patterns and chronic obstructive pulmonary disease among US men. Thorax. 2007;62(9):786-791.
42. Varraso R, Fung TT, Barr RG, Hu FB, Willett W, Camargo CA Jr. Prospective study of dietary patterns and chronic obstructive pulmonary disease among US women. Am J Clin Nutr. 2007; 86(2):488-495. 43. Bentley AR, Kritchevsky SB, Harris TB, et al. Dietary antioxidants and forced expiratory volume in 1 s decline: the Health, Aging and Body Composition study. Eur Respir J. 2012;39(4): 979-984. 44. Wilson DO, Rogers RM, Hoffman RM. Nutrition and chronic lung disease. Am Rev Respir Dis. 1985;132(6):1347-1365.
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Translating Basic Research Into Clinical Practice
Nutrition as a Metabolic Modulator in COPD Annemie M. W. J. Schols, PhD
COPD is an important global health problem. In addition to pulmonary impairment, systemic inflammation, musculoskeletal abnormalities, and cardiovascular comorbidity influence disease burden and mortality risk. Body weight and body composition are important discriminants in classifying disease heterogeneity. The rationale for and efficacy of caloric supplementation in preventing and treating involuntary weight loss is currently well established. For maintenance of muscle and bone tissue, appropriately timed, high-quality protein intake and addressing vitamin D deficiency must be considered. Specific nutrients (eg, n-3 polyunsaturated fatty acids and polyphenolic compounds) may have the pharmacologic potential to boost decreased muscle mitochondrial metabolism and enhance impaired physical performance, particularly when the metabolic stimulus of physical activity alone is limited. At this stage, evidence is insufficient to support an intake of high doses of single nutritional supplements to modulate respiratory pathology, but some small studies have identified micronutrient modulation via the diet as a promising intervention. CHEST 2013; 144(4):1340–1345 Abbreviations: AA 5 amino acid; BCAA 5 branched-chain amino acid; CH 5 carbohydrate; mTOR 5 mammalian target of rapamycin; NF-kB 5 nuclear factor kappa B; PGC-1a 5 peroxisome proliferator-activated receptor coactivator 1a; PPAR 5 peroxisome proliferator-activated receptor; RCT 5 randomized clinical trial; SIRT 5 sirtuin; SPE 5 splanchnic extraction; TNF 5 tumor necrosis factor
is an important global health problem. The COPD lung disorder is characterized by progressive airflow
obstruction resulting from inflammation and remodeling of the airways, and may include development of emphysema. Furthermore, systemic disease manifestations and frequent acute exacerbations influence the disease burden and mortality risk.1 Two recent unbiased statistical approaches to classifying COPD heterogeneity identified body weight as a discriminant2,3 for emphysema, musculoskeletal abnormalities, and cardiovascular comorbidity. Although initially considered as inevitable and a terminal progression of the disease process, there is now convincing evidence that weight loss is not an adaptive mechanism to decrease the metabolic rate in COPD. Conversely, the 2012 Cochrane meta-analysis shows that oral nutritional supplementation improves nutritional status in malnourished patients with COPD without compromising the ventilatory system, and even improves respiratory muscle strength and healthrelated quality of life.4 The incorporation of body composition into nutritional assessment has been a major step forward in understanding systemic COPD pathophysiology and nutritional potential. An impor-
tant role for muscle atrophy and a decreased muscle oxidative metabolism on impaired physical performance have been demonstrated, providing new leads in nutritional supplementation that enhance exercise performance in COPD, not only confined to advanced disease but also in earlier stages.5 In addition, a pivotal role for visceral adiposity and poor dietary quality in COPD risk and progression emerges,6 which positions nutritional intervention as an integral part of disease management, from prevention to chronic respiratory failure (Fig 1). Involuntary Weight Loss and Energy Balance Regulation Weight loss occurs when energy expenditure exceeds energy intake; it may occur gradually or stepwise. In the acute phase of respiratory exacerbations, loss of appetite and diminished dietary intake are often experienced in concert with elevated systemic levels of the appetite-regulating hormone leptin and proinflammatory cytokines.7 However, anorexia is not the primary trigger of a disturbed energy balance in clinically stable disease, because a normal to increased dietary
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intake is reported in underweight patients.8 Moreover, although the normal response to semistarvation is a reduced metabolic rate and depressed whole-body protein turnover, weight-losing patients with COPD often display an elevated resting energy expenditure9 and increased whole-body protein turnover.10,11 In many other chronic inflammatory diseases and cancer, increased resting energy expenditure is associated with a decreased physical activity-induced thermogenesis. In contrast, decreased efficiency of lower-limb muscle contraction12 and decreased ventilatory efficiency contribute to elevated daily energy requirements in COPD. The latter was elegantly illustrated by the association of weight gain with improved lung function and ventilatory efficiency after lung reduction surgery.13 Collectively, this indicates a hypermetabolic state that may contribute to weight loss if energy requirements are not fully met and provides convincing evidence for caloric supplementation to maintain or increase body weight. Early concerns about adverse effects of carbohydrate (CH) supplementation in COPD due to increased CO2 production resulting from CH oxidation loading ventilation have not been substantiated in more recent studies but were observed only after hyperalimentation14; this can easily be avoided by smaller meal portions spread throughout the day. Moreover, from the perspective of enhancing physical performance, there is a strong rationale for prioritizing CH oxidation during exercise training in COPD. Structural and metabolic abnormalities in the skeletal muscles of patients with COPD include reductions in the proportion of type 1 fibers and mitochondrial density, resulting in decreased fat oxidative capacity and increased glucose production.15,16 The functional consequence is early muscle fatigue associated with early lactic acid rise and adenine nucleotide loss, even at the low absolute exercise intensities patients with COPD can achieve. Adequately timed oral nutritional supplements with a higher CH and lower fat composition may be beneficial because digestible CHs are a rapid energy source in the muscle without leading to satiety precluding normal food intake. This is especially relevant for patients with COPD who experience poor appetite because of postprandial shortness Manuscript received February 12, 2013; revision accepted April 1, 2013. Affiliations: From the Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands. Correspondence to: Annemie M. W. J. Schols, PhD, Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0326
Figure 1. COPD from an integrative metabolic perspective.
of breath, because CH-rich supplements induce less shortness of breath than do fat-rich supplements.14 Proof of concept was further provided in a randomized clinical trial (RCT) showing a correlation between increasing CH intake and improved exercise performance after low-intensity aerobic exercise in COPD.17 Nutritional Potential of Boosting Mitochondrial Function High-intensity aerobic exercise improves insulin sensitivity, induces mitochondrial biogenesis in skeletal muscle, and induces loss of visceral fat mass. Not only obese but also normal-weight patients with COPD are at increased risk of these disturbances in metabolic health because of decreased muscle oxidative capacity combined with selectively increased abdominal visceral fat mass.6 However, the efficacy of aerobic exercise may be limited by ventilatory impairment in COPD. Alternatively, or as an adjunct to exercise, the muscle oxidative metabolism may be stimulated nutritionally. Peroxisome proliferator-activated receptors (PPARs) a and d and their coactivator PPAR coactivator 1a (PGC-1a), together with mitochondrial transcription factor-A, promote mitochondrial biogenesis and a slow fiber-type muscle phenotype.18 The protein and mRNA levels of these constituents were decreased in COPD quadriceps muscle.19 Moreover, in vitro research revealed that tumor necrosis factor (TNF)-a, by activation of nuclear factor kappa B (NF-kB), induces a shift in muscle fiber composition toward a fast glycolytic (type 2) isoform and impairs muscle oxidative metabolism by inhibiting the PGC-1a/PPAR signaling pathway.19 Additionally, patients with COPD and elevated levels of muscle TNF-a displayed decreased expression
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of oxidative genes and impaired PGC-1a/PPAR expression compared with patients with COPD and normal muscle TNF-a levels.19 Polyunsaturated fatty acids present in, for example, oils, seafood, and walnuts, are the natural ligands of PPARs, and an RCT showed that polyunsaturated fatty acid supplementation as an adjunct to exercise training indeed significantly enhanced improvement in endurance exercise capacity in COPD.20 This may imply a stimulating effect on muscle fat oxidative metabolism by inhibiting classic NF-kB signaling or stimulating PGC-1a/PPAR signaling. Resveratrol, a natural polyphenolic compound, present in small amounts in the human diet (eg, in mulberries, peanuts, grapes, and red wines), has also been put forward as potential nutraceutical to boost mitochondria. Resveratrol is suggested to impact on the metabolic regulator AMP-activated kinase, which, in turn, affects NAD1 levels, resulting in activation of sirtuin (SIRT) 1, a member of the protein family of NAD1-dependent deacetylases, and activation of PGC1a.21 It was shown in COPD that phospho-AMP-activated kinase levels were lower in patients with a type 1oII fiber shift and correlated with quadriceps endurance.22 Alternatively, cellular NAD1 (re)synthesis may be stimulated directly. Recently, nicotinamide riboside, present in low doses in milk, was found to boost both cellular and mitochondrial NAD1 levels, leading, via different pathways, to synergistic activation of both nuclear SIRT1 and mitochondrial SIRT3.23 Decreased SIRT3 expression has been reported in COPD muscle, which positively correlated with peak oxygen consumption.24 RCTs are needed to investigate the effect of nutraceuticals on mitochondrial function in COPD. The response may be different between peripheral skeletal muscle and the diaphragm, because the diaphragm in COPD is adapted toward an increased oxidative phenotype.25 Nutritional Modulation of Muscle Protein Turnover Generalized atrophy of muscle mass is an inevitable consequence of weight loss, but lower-limb muscle atrophy is also prevalent in normal, stable-weight patients with COPD and is an independent predictor of survival.26 Muscle mass is determined by the net balance of muscle protein synthesis and protein breakdown. Increased whole-body protein turnover has been demonstrated consistently in COPD,10,11 but no recent data exist on the muscle protein synthesis rate, and there is only indirect evidence of an increased muscle protein degradation rate in muscle-wasted patients.27 Analyses of the effector pathways of protein degradation have so far focused on components of the ubiquitin 26S-proteasome system (eg, the E3 ubiquitin-ligase
atrogin-1, polyubiquitinated protein levels), which were found to be consistently elevated.18 Conversely, protein synthesis signaling cues (insulin-like growth factor 1 and phospho-Akt expression levels) are mainly unaltered or, in one study, even increased.18 Nutritional intervention should, therefore, be targeted at the provision of sufficient amino acids (AAs) to support the potentially elevated protein synthesis signaling as a compensatory response to the apparent increases in proteolysis cues. Stimulation of protein synthesis depends on the availability of AAs in the blood stream. Patients with COPD and muscle atrophy have low plasma levels of branched-chain AAs (BCAAs) compared with age-matched control subjects.28 It is well known that BCAAs, in particular leucine, are able to stimulate the anabolic mammalian target of rapamycin (mTOR) signaling cascade and protein synthesis. Recently, it was elegantly shown in vitro that leucine supplementation stimulates myofibrillar protein rather than generic protein accretion in skeletal muscle, and that this involves pretranslational control of myosin heavy chain expression of leucine in an mTORindependent and mTOR-dependent manner.29 As dietary protein is digested and absorbed by the gut, first-pass splanchnic extraction (SPE) of AAs plays a key role in modifying the capacity for protein anabolism during feeding. Several studies have consistently reported an increased first-pass SPE of the AAs leucine and phenylalanine in the elderly, limiting the flow and availability of dietary AA to peripheral tissues. In contrast, a strikingly lower SPE was found in patients with COPD, associated with an enhanced anabolic response to a protein meal, suggesting that the metabolic efficiency of feeding was increased in COPD.30 BCAA supplementation also altered the interorgan metabolism in favor of the peripheral (ie, muscle) compartment.31 Further research is required to investigate whether this potential adaptive mechanism fails in patients with COPD and acute muscle wasting and/or emphysema, because the latter exhibited a depressed muscle protein synthesis32 and a blunted whole-body protein turnover after acute exercise.33 Increased levels of oxidative stress in COPD skeletal muscle have been reported consistently.15 Of the signaling pathways sensitive to oxidative stress and involved in muscle mass regulation, quadriceps biopsy analyses have suggested activation of FOXO, mitogenactivated protein kinase, and NF-kB.15 Mitogenactivated protein kinase and NF-kB signaling is also initiated by inflammation, and increased inflammatory cell infiltration and cytokine expression have been reported in some studies.15 These regulatory pathways of proteolysis or their triggers, oxidative stress and inflammation, could, therefore, be considered as therapeutic targets. Although it has been shown experimentally that NF-kB is sensitive to nutritional intervention
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(ie, the polyunsaturated fatty acids EPA and DHA), therapies to attenuate muscle proteolysis will likely require inclusion of a pharmacologic agent targeting additional signaling axes involved in muscle maintenance regulation. However, to truly understand the cause of muscle wasting at a cellular basis and to develop optimal multimodal intervention strategies, studies analyzing the regulatory and effector pathways of muscle protein turnover should not be limited to a cross-sectional comparison of well-phenotyped subpopulations of COPD, but ideally have a longitudinal design.
The other RCT showed good compliance with a dietary shift, but no association between increasing food and vegetable intake and changes in biomarkers of inflammation and oxidative stress after only 12 weeks of intervention.40 Together, the current evidence strongly suggests that a prudent dietary pattern (rich in fresh vegetables, fruit, oily fish, wine, and cereals) may protect against COPD, especially in smokers, and that dietary intervention in the management of COPD should target a healthy pattern.41-43
Conclusions Micronutrient Deficiency and Supplementation Vitamin D has pleiotropic effects in several tissues and cells, many of which are relevant to COPD. Based on international accepted cutoffs, vitamin D deficiency is highly prevalent in COPD and is associated with decreased lung function and muscle function, osteoporosis, and compromised immune function.34 According to international population guidelines, once vitamin D deficiency has been diagnosed, supplementation is recommended because of its beneficial effects on the bone and its proven benefits in fall-related injuries in populations at risk, such as those with COPD. Daily intakes, in addition to a minimal amount of ultraviolet exposure, vary with age, but a dose of 800 International Units with 1 g of calcium is considered to be largely sufficient. The potential of high-dose supplementation to obtain other effects needs further investigation. A meta-analysis in healthy adults showed a positive effect of vitamin D supplementation on muscle strength in patients with plasma 25(OH)D concentrations , 25 nmol/L only.35 More mechanistic insight was provided in this susceptible group from a study demonstrating a positive effect of vitamin D therapy on skeletal muscle mitochondrial oxidative phosphorylation, which is highly relevant for COPD, as discussed previously.36 Evidence of an inverse association between increased dietary fiber intake and respiratory mortality is convincing.37,38 Dietary fiber has been shown to alter gut immunity and to reduce systemic inflammation, which may be mediated by alterations in the gut microbiome. Epidemiologic evidence furthermore supports a positive relationship between fruit and vegetable intake, lung function, and COPD, which may attenuate oxidative stress. So far, two RCTs have investigated the compliance and efficacy of a dietary shift to higher antioxidant food intake in moderate-to-severe COPD. During a 3-year intervention period, a smaller decline in lung function was shown in patients who shifted from a low to a moderate intake of fruit and vegetables.39
Nutrition in COPD has been topic of extensive scientific research since the landmark paper by Wilson et al44 in 1985. The role of caloric supplementation in preventing and treating weight loss is currently well established. High-quality protein intake and repletion of vitamin D deficiency must be considered for the maintenance of muscle and bone tissue. Specific nutrients may have a pharmacologic potential to enhance physical performance, in particular when physical activity as a metabolic stimulus is limited and when muscle mitochondrial function is impaired. At this stage, evidence is insufficient to support an intake of high doses of single supplements to modulate respiratory pathology, but small studies have identified micronutrient modulation through the diet as a promising intervention.
Acknowledgments Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr Schols has participated in speaking activities and international advisory committees for different nutritional and pharmaceutical companies, sometimes receiving an honorarium.
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