Chronic Obstructive Pulmonary Disease (COPD) is considered a systemic disease that involves pathology in several extra pulmonary tissues. Systemic features in COPD include chronic low-grade systemic inflammation and altered regulation of protein metabolism, which result initially in muscle atrophy only but in later stages in cachexia. Despite the well-recognized importance of treating cachexia in COPD with appropriate nutrition, current nutritional approaches are only partially successful. We recently observed that in order to enhance protein anabolism, manipulation of the composition of proteins and amino acids in nutrition is required in normal-weight COPD. Cachectic COPD patients are characterized by a decreased muscle protein synthesis and an elevated myofibrillar protein breakdown. A substantial number of these patients, characterized by an enhanced systemic inflammatory response, failed to respond to nutritional therapy, which is of clinical relevance as weight gain to nutritional therapy is a significant, independent predictor of mortality in COPD. Eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) are I-3 fatty acids, known to play an anti- inflammatory role through inhibition of cytokine production. EPA+DHA supplementation has been shown to effectively inhibit weight loss, however, weight and muscle mass gain was not achieved both in cancer and COPD. Factors like the low daily dosage of EPA+DHA, the delayed plasma EPA peak after intake, as well as the absence of anabolic agents like proteins and specific amino acids (ie leucine) might explain that EPA+DHA treatment was unsuccessful. Our hypothesis is that there is a unique combination of EPA+DHA, protein and leucine that maximally will stimulate meal-induced net muscle protein synthesis in cachectic COPD patients. In the first experiment, we will examine whether sip feeding of casein protein is preferable above whey protein in the stimulation of whole body net protein synthesis in cachectic COPD patients and whether adding leucine will be of additional benefit. In the second experiment, it will be examined whether daily ingestion of 4000 mg EPA+DHA as compared to 2000 mg EPA+DHA during 4 weeks in cachectic COPD patients will increase the acute response in muscle net protein synthesis to the optimal nutritional mixture as determined in Aim 1. In the third experiment, it will be examined whether daily ingestion of this combination of optimal nutritional mixture and EPA+DHA, as determined in aim 1 and 2, during 8 weeks in cachectic COPD patients will improve nutritional, functional and global clinical outcome as compared to an isocaloric control meal. The combination of plasma and muscle tissue sampling, stable isotope methodology, and assessment of body composition, functional status and quality of life will enable quantification of all endpoints. The results of this study should provide the basis for a new nutritional formulation to support protein anabolism and improve overall outcome in cachectic patients with Chronic Obstructive Pulmonary Disease.

Public Health Relevance

The results of this study should provide the basis for a new nutritional formulation to support protein anabolism and improve overall outcome in cachectic patients with Chronic Obstructive Pulmonary Disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095903-03
Application #
8104012
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Punturieri, Antonello
Project Start
2009-08-06
Project End
2012-03-31
Budget Start
2011-07-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$362,500
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Walker, Dillon K; Thaden, John J; Wierzchowska-McNew, Agata et al. (2017) Determination of ?-hydroxy-?-methylbutyrate concentration and enrichment in human plasma using chemical ionization gas chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 1040:233-238
de Betue, Carlijn T I; Garcia Casal, Xiomara C; van Waardenburg, Dick A et al. (2017) 24-Hour protein, arginine and citrulline metabolism in fed critically ill children - A stable isotope tracer study. Clin Nutr 36:876-887
Jonker, Renate; Deutz, Nicolaas Ep; Erbland, Marcia L et al. (2017) Effectiveness of essential amino acid supplementation in stimulating whole body net protein anabolism is comparable between COPD patients and healthy older adults. Metabolism 69:120-129
Engelen, Mariëlle P K J; van der Meij, Barbara S; Deutz, Nicolaas E P (2016) Protein anabolic resistance in cancer: does it really exist? Curr Opin Clin Nutr Metab Care 19:39-47
Walker, Dillon K; Thaden, John J; Deutz, Nicolaas E P (2015) Application of gas chromatography-tandem mass spectrometry (GC/MS/MS) for the analysis of deuterium enrichment of water. J Mass Spectrom 50:838-43
Deutz, Nicolaas E P; Bauer, Jürgen M; Barazzoni, Rocco et al. (2014) Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN Expert Group. Clin Nutr 33:929-36
Jonker, Renate; Deutz, Nicolaas E P; Erbland, Marcia L et al. (2014) Hydrolyzed casein and whey protein meals comparably stimulate net whole-body protein synthesis in COPD patients with nutritional depletion without an additional effect of leucine co-ingestion. Clin Nutr 33:211-20
Engelen, Mariëlle P K J; Com, Gulnur; Deutz, Nicolaas E P (2014) Protein is an important but undervalued macronutrient in the nutritional care of patients with cystic fibrosis. Curr Opin Clin Nutr Metab Care 17:515-20
Deutz, Nicolaas E; Wolfe, Robert R (2013) Is there a maximal anabolic response to protein intake with a meal? Clin Nutr 32:309-13
Engelen, M P K J; De Castro, C L N; Rutten, E P A et al. (2012) 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 31:616-24

Showing the most recent 10 out of 12 publications