Chronic Obstructive Pulmonary Disorder and Acute Exercise

Study Overview
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Brief Summary
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For this study a resistance bout will be performed in order to promote the robust response of protein synthesis. Type II muscle fibers often exhibit more atrophy than type I fibers in COPD subjects therefore specifically targeting them in an exercise protocol could have more beneficial outcome for these individuals.

Detailed Description
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In this study, the following hypothesis will be tested: A bout of resistance exercise will affect the acute and 24h response in whole-body protein and amino acid metabolism and cognitive function as compared to baseline values in COPD patients and healthy subjects. To do this, subjects will complete a baseline visit in which they receive stable amino acid tracers. The next day they will complete a one-time resistance exercise with an immediate measurement of the amino acid tracers, and return 24 hours after exercise to repeat amino acid tracer measurements. This project will provide important clinical information on the whole body protein and amino acid metabolic response to acute resistance exercise in elderly subjects with COPD, as well as, the exercise induced changes in physical and cognitive function, and absolute muscular strength capacity in this population. In this way, this study will provide preliminary data for the development of standardized, repeatable resistance exercise protocols that will stop the process of ongoing muscle loss and improve metabolism and function in COPD subjects.

Official Title
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The Effects of Acute Resistance Exercise on Protein and Amino Acid Metabolism in Chronic Obstructive Pulmonary Disease

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Other: stable amino acid infusion
* Other: acute exercise with amino acid infusion
* Other: 24-hour post exercise amino acid infusion


Participation Criteria
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Eligibility Criteria
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Inclusion criteria COPD subjects: Ability to walk, sit down and stand up independently Age 45 years or older Ability to lie in supine or elevated position for 4 hours Diagnosis of moderate to very severe chronic airflow limitation and compliant to the following criteria: FEV1 < 70% of reference FEV1 Clinically stable condition and not suffering from a respiratory tract infection or exacerbation of their disease (defined as a combination of increased cough, sputum purulence, shortness of breath, systemic symptoms such as fever, and a decrease in FEV1 > 10% compared with values when clinically stable in the preceding year) at least 4 weeks prior to the first test day Shortness of breath on exertion Willingness and ability to comply with the protocol Inclusion criteria healthy subjects: Healthy male or female according to the investigator's or appointed staff's judgment Ability to walk, sit down and stand up independently Age 45 years or older Ability to lay in supine or elevated position for 4 hours No diagnosis of COPD Willingness and ability to comply with the protocol Exclusion Criteria all subjects: Any condition that may interfere with the definition 'healthy subject' according to the investigator's judgment (healthy subjects only) Established diagnosis of malignancy History of untreated metabolic diseases including hepatic or renal disorder Presence of acute illness or metabolically unstable chronic illness Presence of fever within the last 3 days Body mass index >40 kg/m2 (healthy subjects only) Any other condition according to the PI or nurse that was found during the screening visit, that would interfere with the study or safety of the patient Use of protein or amino acid containing nutritional supplements within 5 days of first study day Previous injury that could interfere with participation in resistance exercise protocol Use of short course of oral corticosteroids within 4 weeks preceding first study day Failure to give informed consent or Investigator's uncertainty about the willingness or ability of the subject to comply with the protocol requirements (Possible) pregnancy Already enrolled in another clinical trial and that clinical trial interferes with participating in this study

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy<br>screening visit: body weight and composition by DXA, height, and vital signs will be assessed. study day(s): may include combinations of stable isotope infusions with blood draws, acute exercise, cognition testing | Other: stable amino acid infusion<br>* stable isotopes Such as L-[ring-13C6]-Phenylalanine, L-[ring-D4]Tyrosine, L-[Methyl-D3]Tau-Methylhistidine, trans-[2,5,5-D3]4-Hydroxy-L-proline, L-[Guanido-15N2]-Arginine, L-[4,4,5,5-D4-5-13C]Citruline, L-13C5 -Ornithine, L-15N2-Glutamine, L-[1,2-13C2]Glutamic Acid, 1-13C-Glycine, L-15N3-Histidine, L-13C6-Leucine, L-[methyl-D3]Methionine, α-1-13C-ketoisocaproic acid, L-1-13C-Methionine, DL-[3,3,4,4-D4]Homocysteine, L-[1,2-13C2]Taurine, L-(Indole-D5)Tryptophan, 13C-Urea, L-1-13C-Isoleucine, L-13C5-Valine, α-[Dimethyl-13C2]ketoisovaleric acid, 2-keto-3-methyl-13C6-pentanoate, 3-hydroxy-[3,4-methyl-13C3]isovaleric acid, 13C3-glycerol is given IV simultaneously<br>Other: acute exercise with amino acid infusion<br>* resistance exercise of each limb (i.e., leg (right/left); arm (right/left) on an isokinetic exercise machine allowing control of velocity, force, etc. with stable isotopes such as L-[ring-13C6]-Phenylalanine, L-[ring-D4]Tyrosine, L-[Methyl-D3]Tau-Methylhistidine, trans-[2,5,5-D3]4-Hydroxy-L-proline, L-[Guanido-15N2]-Arginine, L-[4,4,5,5-D4-5-13C]Citruline, L-13C5 -Ornithine, L-15N2-Glutamine, L-[1,2-13C2]Glutamic Acid, 1-13C-Glycine, L-15N3-Histidine, L-13C6-Leucine, L-[methyl-D3]Methionine, α-1-13C-ketoisocaproic acid, L-1-13C-Methionine, DL-[3,3,4,4-D4]Homocysteine, L-[1,2-13C2]Taurine, L-(Indole-D5)Tryptophan, 13C-Urea, L-1-13C-Isoleucine, L-13C5-Valine, α-[Dimethyl-13C2]ketoisovaleric acid, 2-keto-3-methyl-13C6-pentanoate, 3-hydroxy-[3,4-methyl-13C3]isovaleric acid, 13C3-glycerol is given IV simultaneously<br>Other: 24-hour post exercise amino acid infusion<br>* stable isotopes such as L-[ring-13C6]-Phenylalanine, L-[ring-D4]Tyrosine, L-[Methyl-D3]Tau-Methylhistidine, trans-[2,5,5-D3]4-Hydroxy-L-proline, L-[Guanido-15N2]-Arginine, L-[4,4,5,5-D4-5-13C]Citruline, L-13C5 -Ornithine, L-15N2-Glutamine, L-[1,2-13C2]Glutamic Acid, 1-13C-Glycine, L-15N3-Histidine, L-13C6-Leucine, L-[methyl-D3]Methionine, α-1-13C-ketoisocaproic acid, L-1-13C-Methionine, DL-[3,3,4,4-D4]Homocysteine, L-[1,2-13C2]Taurine, L-(Indole-D5)Tryptophan, 13C-Urea, L-1-13C-Isoleucine, L-13C5-Valine, α-[Dimethyl-13C2]ketoisovaleric acid, 2-keto-3-methyl-13C6-pentanoate, 3-hydroxy-[3,4-methyl-13C3]isovaleric acid, 13C3-glycerol is given IV simultaneously<br>|
| Experimental: Chronic Obstructive Pulmonary Disorder<br>screening visit: body weight and composition by DXA, height, and vital signs will be assessed. study day(s): may include combinations of stable isotope infusions with blood draws, acute exercise, cognition testing | Other: stable amino acid infusion<br>* stable isotopes Such as L-[ring-13C6]-Phenylalanine, L-[ring-D4]Tyrosine, L-[Methyl-D3]Tau-Methylhistidine, trans-[2,5,5-D3]4-Hydroxy-L-proline, L-[Guanido-15N2]-Arginine, L-[4,4,5,5-D4-5-13C]Citruline, L-13C5 -Ornithine, L-15N2-Glutamine, L-[1,2-13C2]Glutamic Acid, 1-13C-Glycine, L-15N3-Histidine, L-13C6-Leucine, L-[methyl-D3]Methionine, α-1-13C-ketoisocaproic acid, L-1-13C-Methionine, DL-[3,3,4,4-D4]Homocysteine, L-[1,2-13C2]Taurine, L-(Indole-D5)Tryptophan, 13C-Urea, L-1-13C-Isoleucine, L-13C5-Valine, α-[Dimethyl-13C2]ketoisovaleric acid, 2-keto-3-methyl-13C6-pentanoate, 3-hydroxy-[3,4-methyl-13C3]isovaleric acid, 13C3-glycerol is given IV simultaneously<br>Other: acute exercise with amino acid infusion<br>* resistance exercise of each limb (i.e., leg (right/left); arm (right/left) on an isokinetic exercise machine allowing control of velocity, force, etc. with stable isotopes such as L-[ring-13C6]-Phenylalanine, L-[ring-D4]Tyrosine, L-[Methyl-D3]Tau-Methylhistidine, trans-[2,5,5-D3]4-Hydroxy-L-proline, L-[Guanido-15N2]-Arginine, L-[4,4,5,5-D4-5-13C]Citruline, L-13C5 -Ornithine, L-15N2-Glutamine, L-[1,2-13C2]Glutamic Acid, 1-13C-Glycine, L-15N3-Histidine, L-13C6-Leucine, L-[methyl-D3]Methionine, α-1-13C-ketoisocaproic acid, L-1-13C-Methionine, DL-[3,3,4,4-D4]Homocysteine, L-[1,2-13C2]Taurine, L-(Indole-D5)Tryptophan, 13C-Urea, L-1-13C-Isoleucine, L-13C5-Valine, α-[Dimethyl-13C2]ketoisovaleric acid, 2-keto-3-methyl-13C6-pentanoate, 3-hydroxy-[3,4-methyl-13C3]isovaleric acid, 13C3-glycerol is given IV simultaneously<br>Other: 24-hour post exercise amino acid infusion<br>* stable isotopes such as L-[ring-13C6]-Phenylalanine, L-[ring-D4]Tyrosine, L-[Methyl-D3]Tau-Methylhistidine, trans-[2,5,5-D3]4-Hydroxy-L-proline, L-[Guanido-15N2]-Arginine, L-[4,4,5,5-D4-5-13C]Citruline, L-13C5 -Ornithine, L-15N2-Glutamine, L-[1,2-13C2]Glutamic Acid, 1-13C-Glycine, L-15N3-Histidine, L-13C6-Leucine, L-[methyl-D3]Methionine, α-1-13C-ketoisocaproic acid, L-1-13C-Methionine, DL-[3,3,4,4-D4]Homocysteine, L-[1,2-13C2]Taurine, L-(Indole-D5)Tryptophan, 13C-Urea, L-1-13C-Isoleucine, L-13C5-Valine, α-[Dimethyl-13C2]ketoisovaleric acid, 2-keto-3-methyl-13C6-pentanoate, 3-hydroxy-[3,4-methyl-13C3]isovaleric acid, 13C3-glycerol is given IV simultaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in net whole-body protein synthesis | Change in whole-body protein synthesis rate | 2, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210 and 240 ± 5 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| glutamate related metabolism |  | 2, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210 and 240 ± 5 minutes | 
| tryptophan related metabolism |  | 2, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210 and 240 ± 5 minutes | 
| arginine related metabolism |  | 2, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210 and 240 ± 5 minutes | 
| leucine related metabolism |  | 2, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210 and 240 ± 5 minutes | 
| taurine related metabolism |  | 2, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210 and 240 ± 5 minutes | 
| Body Composition | Body composition as measured by Dual-Energy X-ray Absorptiometry | 15 minutes on screening or study day 1 | 
| changes in skeletal muscle fatigue | kin-com 1-leg test | on study day 1 and change from day 2 and day 3 | 
| Group differences in state of mood as measured by the Hospital Anxiety and Depression Scale (HADS) | a fourteen item self-assessment scale. Seven of the items related to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. | 1 day | 
| Group differences in attention and executive functions as measured by Stroop Color-Word Test (SCWT) | a word page with words printed in black ink, a color page with blocks printed in color, and a color-word page where the color and the word do not match. The examinee reads the words or names the ink colors as quickly as possible within a time limit. Measures selective attention and inhibitory control. The total time in seconds was reported for each trial. | on study day 1 and change from day 2 and day 3 | 
| Group differences in learning and memory as measured by Digit Span | recall of numbers in the same order (Digit Forward) and in reverse order (Digit Backward). Measures auditory attention and verbal working memory. | on study day 1 and change from day 2 and day 3 | 
| Group differences in attention and executive functions as measured by Digit Symbol Modalities Test | Using a legend with nine symbols that correspond to nine different numbers, the examinee is asked to fill in as many blank squares as possible by copying the corresponding number in each box, indexed by a symbol within a 90 sec time limit. | on study day 1 and change from day 2 and day 3 | 
| Group differences in activity as measured by Physical Activity Scale for the Elderly (PASE) | This questionnaire is intended for use in an elderly population and focuses on 3 types of activities: leisure time activities, household activities and work-related activities. | study day 1 | 
| 24 hour diet recall | The subject is asked to recall in detail all the food and drink consumed during the 24 hours prior to the test day. | study day 1 | 
| appetite questionnaire | The subject is asked to rate various aspects of their appetite as relates to overall health | study day 1 |