Muscle Perfusion and Protein Metabolism in Elderly

A Phase I Trial Examining Muscle Perfusion and Protein Metabolism in Elderly and Young

The purpose of this study was to examine the role skeletal muscle perfusion plays in mediating muscle protein synthesis in healthy older and younger individuals. The investigators hypothesized that normalization of muscle perfusion in older men and women via exercise or infusion of a vasodilator would enhance nutritive flow and skeletal muscle protein synthesis in the elderly similar to that of their younger counterparts.

Study Overview

• Status: Completed
• Conditions: Aging
• Intervention / Treatment: Other: Aerobic Exercise; Drug: Sodium Nitroprusside; Dietary supplement: Amino Acid Drink

Detailed Description

The purpose of this study was to examine muscle protein metabolism in healthy young and elderly subjects during pharmacologic vasodilation of the lower limb vasculature in combination with increased amino acids delivery. We obtained femoral arteriovenous blood samples and v. lateralis muscle biopsies during a primed continuous infusion of L-[ring-13C6] Phenylalanine. Muscle protein kinetics were measured in the basal state and during a 180 min infusion of sodium nitroprusside (SNP) and amino acids (Premsol 10%) (SNP+AA). Skeletal muscle microvascular recruitment and flow were measured during the basal state and SNP+AA using contrast-enhanced ultrasound (CEU).

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All inclusion criteria must be fulfilled throughout the study. At enrollment, subjects must fit the following criteria:

1. Age: young 18-40 yrs; elderly 60-85 yrs.
2. Availability of transportation (i.e., subjects must be able to provide their own transportation to UTMB).
3. Ability to sign informed consent (score >24 on 30 item mini-mental status exam and no errors on assessment of judgment).

Exclusion Criteria:

None of the following exclusion criteria should be present at enrollment or throughout the study:

1. Patients with limiting or unstable angina or who demonstrate cardiac abnormalities such as > 0.2 mV horizontal or downsloping ST segment depression, frequent arrhythmias (>10 PVC/min), or valvular disease.
2. Any patient with atrial fibrillation, history of syncope, angina, or congestive heart failure.
3. Patients with vascular disease, as determined by the presence of risk factors of peripheral atherosclerosis (i.e., hypertension, obesity, uncontrolled diabetes, and evidence of venous or arterial insufficiency upon palpation of femoral, popliteal, and pedal arteries).
4. Peripheral vascular disease as determined by history or abnormal ankle-brachial index by Doppler (< 1.0).
5. Any subject with blood pressure on three consecutive measurements taken at rest on separate occasions that has a systolic pressure >170 mm Hg or a diastolic blood pressure >100 mm Hg will be excluded. Subjects will not be included if they are taking blood pressure medication and have a blood pressure above these criteria.
6. Any person HIV-seropositive, with active hepatitis, or any other immunosuppressive or autoimmune disease.
7. Any patient taking beta blockers, vasodilators, angiotensin-converting enzyme inhibitors, calcium channel blockers, or alpha blockers.
8. Any patient with uncontrolled metabolic diseases including any patient with liver or renal disease.
9. Glucose intolerance: fasting plasma glucose concentration 110-126 mg/dL (6.1-7 mmol/L) and/or 2-h plasma glucose 140-200 mg/dL (7.8-11.1 mmol/L) during oral glucose tolerance test (OGTT).
10. Currently in muscle strengthening program.
11. Total knee replacement or moderate to severe degenerative joint disease of knees.
12. Anemia (hemoglobin <13 g/dL in males or <12 g/dL in females).
13. Any history of hypo- or hyper-coagulation disorders, including patients taking Coumadin or with a history of deep venous thrombosis (DVT) or pulmonary embolism (PE) at any point in their lifetimes.
14. Currently taking aspirin and cannot stop for 7 days (i.e., medical indication for continued aspirin such as transient ischemic attacks).
15. Presence of acute illness or metabolically unstable chronic illness.
16. Heart disease requiring therapy or recent myocardial infarction (less than 1 year)
17. Currently on weight-loss diet.
18. Active cancer or in short-term remission (less than 3 years).
19. Alcohol or drug abuse.
20. History of >20 packs per year cigarette smoking.
21. Recent (within 6 months) ingestion or injection or transdermal administration of anabolic steroids, corticosteroids, estrogens, or progestagens.
22. History of falls (1 fall in the past year which required medical attention, or more than 2 falls/year regardless of severity).
23. Allergy to iodides, penicillin or shellfish.
24. Any subject with a know hypersensitivity to octafluoropropane.
25. Any subject with a cardiac shunt.
26. Any subject with chronic obstructive pulmonary disease (COPD).

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Young Aerobic Exercise; 45 minutes of treadmill walking at 40% VO2 peak	Other: Aerobic Exercise; 45 minuties of treadmill walking was completed at 40% VO2 peak
Active Comparator: Elderly Aerobic Exercise; 45 minutes of treadmill walking at 40% VO2 peak	Other: Aerobic Exercise; 45 minuties of treadmill walking was completed at 40% VO2 peak
Active Comparator: Young Sodium Nitroprusside; Sodium Nitroprusside given in a constant infusion for 180 minutes at a rate of 0.114 ug/kg/min	Drug: Sodium Nitroprusside; Sodium Nitroprusside was given in a constant infusion for 180 minutes at a rate of 0.114 ug/kg/min; Other Names: Nitropress
Active Comparator: Elderly Sodium Nitoprusside; Sodium Nitroprusside given in a constant infusion for 180 minutes at a rate of 0.114 ug/kg/min	Drug: Sodium Nitroprusside; Sodium Nitroprusside was given in a constant infusion for 180 minutes at a rate of 0.114 ug/kg/min; Other Names: Nitropress
Active Comparator: Elderly Sodium Nitroprusside and Amino Acid Drink; Sodium Nitroprusside given in a constant infusion for 180 minutes at a rate of 0.114 ug/kg/min and 7.5g amino acid drink taken orally	Drug: Sodium Nitroprusside; Sodium Nitroprusside was given in a constant infusion for 180 minutes at a rate of 0.114 ug/kg/min; Other Names: Nitropress; Dietary supplement: Amino Acid Drink; 7.5 gram Amino Acid drink

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mixed Muscle Fractional Synthesis Rate (FSR)	The rate at which the body makes new muscle was assessed by determining the fractional synthesis rate (FSR). This technique determines how quickly new amino acids are used to make muscle. In this technique, a special (but natural and non-radioactive) version of an amino acid is infused into the blood. This special version of the amino acid is heavier than the most common version the same amino acid. This property allows it to be identified in a muscle sample. By determining how much of the special amino acid has accumulated over time in a muscle sample, the fractional synthesis rate can be determined. For example, if the rate were such that 1 of every 100 amino acids were of the special type after 1 day, the fractional synthesis rate would be 1% per day. In other words, 1/100 of the muscle would be newly made each day.	Acute ( 8 hours)

Collaborators and Investigators

• Sponsor: The University of Texas Medical Branch, Galveston
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Melinda Sheffield-Moore, PhD, UTMB

Study record dates

Study Major Dates

• Study Start: May 1, 2003
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: July 22, 2009
• First Submitted That Met QC Criteria: July 23, 2009
• First Posted (Estimate): July 24, 2009

Study Record Updates

• Last Update Posted (Estimate): February 3, 2016
• Last Update Submitted That Met QC Criteria: January 5, 2016
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: exercise; metabolism; sodium nitroprusside
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Nitric Oxide Donors; Nitroprusside
• Other Study ID Numbers: 03-213; R01AG021539 (U.S. NIH Grant/Contract)