Role of Skeletal Muscle Nitric Oxide Production in Age-related Fatigue and Fatigability

NCT ID: NCT01059994

Last Updated: 2019-02-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-01-31
• Study Completion Date: 2013-07-31

Brief Summary

This is a pilot study funded by the National Institutes of Health. In this project, we will investigate the potential effect of skeletal muscle nitric oxide (NO) production on muscle strength and physical function in older individuals. We propose to test a new method that may enable simultaneous determination of both vascular and skeletal muscle NO production for the first time in humans. Further, we will determine whether augmentation of NO-mediated responses, by administration of sildenafil citrate (Viagra), reduces fatigue and fatigability in older individuals.

Detailed Description

Fatigue is highly prevalent and associated with future mortality in older individuals. Even in non-disabled older persons, fatigue may be the primary reason for activity limitation. However, understanding the etiology of fatigue in this population has been hampered by differing or imprecise definitions of fatigue. As a result, the term fatigue has been proposed to refer to the subjective experience of tiredness or lack of energy, whereas the term fatigability should refer to the susceptibility to fatigue induced by activity of any kind (mental, physical, etc). Skeletal muscle activity can contribute to the perception of overall fatigue as well as produce a type of localized fatigue within skeletal muscle. Skeletal muscle fatigue is defined as a decline in skeletal muscle performance resulting from muscle activity.

We hypothesize that skeletal muscle NO-mediated responses are reduced with aging due to decreased skeletal muscle NO production. NO is well-known to elicit vasodilation through stimulation of cGMP signaling, and NO-mediated changes in muscle perfusion may influence both skeletal muscle and overall fatigue. To measure skeletal muscle NO production, we will infuse a stable isotope tracer of arginine, the precursor of NO, and measure its conversion across the leg and in skeletal muscle to citrulline (which is another product of the reaction that produces NO). If successful, this method will allow the study of relative changes in vascular and muscle NO production that occur with aging and other conditions (e.g., hypertension, Duchenne muscular dystrophy). We will also determine whether age-related differences in muscle perfusion and NO-cGMP signaling exist between younger and older groups. As impaired redox homeostasis and ryanodine receptor S-nitrosylation and phosphorylation have been implicated in skeletal muscle fatigue, we will assess skeletal muscle redox homeostasis and ryanodine receptor S-nitrosylation in these experiments. We hypothesize that aging will shift muscle redox homeostasis to a more oxidized state.

Conditions

Fatigue; Aging

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

placebo sildenafil young

Younger subjects (ages 20-35) were administered placebo sildenafil orally daily for 1 week.

Group Type: PLACEBO_COMPARATOR

Placebo sildenafil

Intervention Type: DRUG

Oral, daily, 1 week.

sildenafil young

Younger subjects (ages 20 -35) were administered sildenafil daily (25 mg/day) orally for 1 week.

Group Type: EXPERIMENTAL

Sildenafil

Intervention Type: DRUG

oral, 25mg, daily for 1 week

placebo sildenafil older

Older subjects (ages 60-80) were administered placebo sildenafil orally daily for 1 week.

Group Type: PLACEBO_COMPARATOR

Placebo sildenafil

Intervention Type: DRUG

Oral, daily, 1 week.

sildenafil older

Older subjects (ages 60 - 80) were administered sildenafil daily (25 mg/day) orally for 1 week.

Group Type: EXPERIMENTAL

Sildenafil

Intervention Type: DRUG

oral, 25mg, daily for 1 week

Interventions

Placebo sildenafil

Oral, daily, 1 week.

Intervention Type: DRUG

Sildenafil

oral, 25mg, daily for 1 week

Intervention Type: DRUG

Other Intervention Names

Viagra; Viagra

Eligibility Criteria

Inclusion Criteria

• 1. Age 20-35 yrs, and 60-80 yrs.
• 2. Ability to sign consent form (score >23 on the 30-item Mini Mental State Examination, MMSE)
• 3. Stable body weight for at least 3 months

Exclusion Criteria

• 1. Physical dependence or frailty (impairment in any of the Activities of Daily Living (ADL), history of falls (>2/year) or significant weight loss in the past year)
• 2. Exercise training (>2 weekly sessions of moderate to high intensity aerobic or resistance exercise)
• 3. Pregnancy
• 4. Significant heart, liver, kidney, blood or respiratory disease
• 5. Peripheral vascular disease
• 6. Diabetes mellitus or other untreated endocrine disease
• 7. Active cancer
• 8. Use of nitrates
• 9. Recent (within 6 months) treatment with anabolic steroids, or corticosteroids.
• 10. Alcohol or drug abuse
• 11. Severe depression (>5 on the 15-item Geriatric Depression Scale, GDS)
• 12. Cardiac abnormalities such as a cardiac shunt or previously diagnosed pulmonary hypertension.
• 13. Systolic blood pressure <100 or >150, diastolic blood pressure <60 or >90.

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

The University of Texas Medical Branch, Galveston

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

William Durham, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University of Texas

Locations

University of Texas Medical Branch

Galveston, Texas, United States

Countries

United States

Other Identifiers

09-213

Identifier Type: -

Identifier Source: org_study_id