# title
Functional and metabolic effects of omega-3 polyunsaturated fatty acid supplementation and the role of -hydroxy--methylbutyrate addition in chronic obstructive pulmonary disease: A randomized clinical trial.

# abstract
INTRODUCTION: Short-term (4 weeks) supplementation with n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has recently been shown to improve protein metabolism in a dose dependent way in normal weight patients with Chronic Obstructive Pulmonary Disease (COPD). Furthermore, EPA/DHA supplementation was able to increase extremity lean soft tissue but not muscle function. No studies are available combining n-3 PUFAs and the leucine metabolite -hydroxy--methylbutyrate (HMB) supplementation in chronic clinical conditions. Whether adding HMB to daily EPA/DHA supplementation for 10 weeks enhances muscle and brain health, daily functional performance, and quality of life of patients with COPD by further improving their protein and amino acid homeostasis remains unknown. METHODS: Patients with COPD (GOLD: II-IV, n=46) received daily for 10 weeks, according to a randomized double-blind placebo-controlled three-group design, EPA/DHA (n=16), EPA/DHA to which HMB was added (n=14), or placebo (n=16). The daily dose of 2.0g of EPA/DHA or soy+corn oil as the placebo was provided via gel capsules, and 3.0g of Ca-HMB or maltodextrin as placebo as powders. At pre- and post-intervention, a pulse mixture of multiple amino acids was administered to measure postabsorptive net protein breakdown (netPB as primary endpoint) and whole body production (WBP) and conversion rates of the amino acids. As secondary endpoints, lean soft tissue and fat mass were assessed by dual-energy X-ray absorptiometry, upper and lower muscle function by handgrip and single leg isokinetic dynamometry, brain (cognitive, wellbeing) health by assessments, daily functional performance by measuring 6-min walk distance, 4-m gait speed, and postural balance, and quality of life by questionnaire. Plasma enrichments and concentrations were analyzed by LC-MS/MS, and systemic inflammatory profile and metabolic hormones by Luminex. RESULTS: HMB+EPA/DHA but not EPA/DHA supplementation increased postabsorptive netPB (p=0.028), and WBPs of glutamine (p=0.024), taurine (p=0.039), and tyrosine (p=0.036). Both EPA/DHA and HMB+EPA/DHA supplementation resulted in increased WBP of phenylalanine (p<0.05). EPA/DHA but not HMB+EPA/DHA was able to increase WBP of arginine (p=0.030), citrulline (p=0.008), valine (p=0.038), and conversion of citrulline to arginine (p=0.009). Whole body and extremity fat mass were reduced after HMB+EPA/DHA supplementation only, whereas lean soft tissue was increased after EPA/DHA (p=0.049) and HMB+EPA/DHA (p=0.073). No other significant findings were observed. Reductions in several proinflammatory cytokines were observed in the HMB+EPA/DHA group including IL-2, IL-17, IL-6, IL-12P40, and TNF- (p<0.05). CONCLUSIONS: Ten weeks of supplementation with 2g of EPA/DHA daily is sufficient to induce muscle gain in COPD but HMB is needed to induce fat loss. Whether HMB is solely responsible for the fat mass loss or has a synergistic effect with EPA/DHA remains unclear. The increase in net protein breakdown observed with HMB+EPA/DHA supplementation may indicate a beneficial enhanced protein turnover cycling associated with increased lean soft tissue. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; NCT03796455.

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Texas A&M University Naresh K. Vashisht College of Medicine

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College of Education and Human Development

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Center for Translational Research in Aging and Longevity

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College of Education and Human Development

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Center for Translational Research in Aging and Longevity

# authorList[]
Engelen, M., Simbo, S. Y., Ruebush, L. E., Thaden, J. J., Ten Have, G., Harrykissoon, R. I., ... Deutz, N.