This study is funded by the Moody Endowment. In this project, we will investigate the potential effect of skeletal muscle nitric oxide (NO) production on skeletal muscle anabolism, muscle strength, physical function, and body composition in older individuals. Further, we will determine whether augmentation of NO-mediated signaling reduces fatigue and fatigability.
The Investigators hypothesize that upregulation of skeletal muscle NO-cGMP mediated responses through phosphodiesterase (PDE) inhibition by sildenafil or tadalafil causes an acute anabolic response of skeletal muscle protein synthesis. NO is well-known to elicit vasodilation through stimulation of cGMP signaling, and NO-mediated changes in muscle perfusion may influence both skeletal muscle anabolism and perceptual fatigue. To measure skeletal muscle protein synthesis, we will infuse a stable isotope tracer of phenylalanine and measure its incorporation into skeletal muscle proteins following a dose of sildenafil, tadalafil, or placebo. The Investigators will also determine whether differences exist between men and women in response to PDE inhibition. As skeletal muscle NO-cGMP signaling has been implicated in fatigue responses, we will assess the acute effect of sildenafil and tadalafil on fatigue. Fatigue can be manifested both as a performance deficit at a local level (e.g., a reduced ability of skeletal muscle to produce power or force) as well as a subjective experience of lacking physical or mental energy. Accordingly, we will use more than one means (skeletal muscle performance, fatigue questionnaires, accelerometers) to study fatigue. The Investigators hypothesize that sildenafil or tadalafil will acutely reduce exercise-associated fatigability and skeletal muscle fatigue development
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
30
50 mg/day for 4 weeks
10 mg/day for 4 weeks.
Placebo 1 capsule per day for four weeks.
University of Texas Medical Branch
Galveston, Texas, United States
Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Placebo
Isokinetic Fatigue Measure (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 50 contractions were performed at 100% force, one contraction every second. Isokinetic fatigue will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. Data is presented as mean maximum force over all 50 kicks.
Time frame: after 4 weeks of placebo
Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Active Drug
Isokinetic Fatigue Measure (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 50 contractions were performed at 100% force, one contraction every second. Isokinetic fatigue will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug. Data is presented as mean maximum force over all 50 kicks.
Time frame: after 4 weeks of active drug
Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Placebo
The fatigue rating scale is a scale from 0 to 10 with 0 being no fatigue at all and 10 being the worst fatigue the subject can imagine. The subject is asked to rate their level of fatigue in their leg. This test was performed before and immedicately after the Biodex leg fatigue test after 4 weeks of placebo. Data is presented as change in scale from pre fatigue test to post fatigue test, with a higher score indicating a greater level of fatigue.
Time frame: after 4 weeks of placebo
Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Active Drug
The fatigue rating scale is a scale from 0 to 10 with 0 being no fatigue at all and 10 being the worst fatigue the subject can imagine. The subject is asked to rate their level of fatigue in their leg. This test was performed before and immedicately after the Biodex leg fatigue test. Data is presented as change in scale from pre fatigue test to post fatigue test, with a higher score indicating a greater level of fatigue.
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Time frame: after 4 weeks of active drug
Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo
Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 5 seconds of force production for each contraction and 15 seconds of rest. 1 set of 3 contractions at 100% force performed. Isometric strength was measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of placebo
Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug.
Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 5 seconds of force production for each contraction and 15 seconds of rest. 1 set of 3 contractions at 100% force performed. Isometric strength was measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of active drug
Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo.
Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 1 set of 3 contractions were performed at 100% force. Isokinetic strength will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of placebo
Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug
Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 1 set of 3 contractions were performed at 100% force. Isokinetic strength will be measured at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of active drug
Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0.
Lean Body Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 0
Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4.
Lean Body Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 4
Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8.
Lean Body Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 8
Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0.
Fat Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 0
Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4.
Fat Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 4
Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8.
Fat Mass is calculated from a whole body scan measured on a dual energy x-ray absorptiometry.
Time frame: week 8
Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Placebo
Walking performance will be assessed during 2 minutes of walking in long corridor hallways. Subjects will be asked to walk at 100% effort (as quickly as they can safely walk without running) for 2 minutes. Distance traveled for the 2 minutes will be recorded. The walking test will be completed at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of placebo
Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Active Drug
Walking performance will be assessed during 2 minutes of walking in long corridor hallways. Subjects will be asked to walk at 100% effort (as quickly as they can safely walk without running) for 2 minutes. Distance traveled for the 2 minutes will be recorded. The walking test will be completed at week 4 and week 8. Depending on grouping, the week 4 and week 8 measures may be placebo or active drug. Data will be reported as after 4 weeks of placebo or after 4 weeks of active drug.
Time frame: after 4 weeks of active drug
Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 0
Fatigue symptoms will be measured using the 30-item Multidimensional Fatigue Symptom Inventory - Short Form, a validated measure that yields one overall score of total fatigue calculated using five sub scales (general, physical, emotional, mental, vigor). With the exception of the vigor sub scale, higher scores indicate greater fatigue. Total fatigue score is calculated by summing the sub categories (general, physical, emotional and mental) and subtracting vigor. Total scores range from -24 to 96, with a higher score indicating more fatigue.
Time frame: Week 0
Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 4
Fatigue symptoms will be measured using the 30-item Multidimensional Fatigue Symptom Inventory - Short Form, a validated measure that yields one overall score of total fatigue calculated using five sub scales (general, physical, emotional, mental, vigor). With the exception of the vigor sub scale, higher scores indicate greater fatigue. Total fatigue score is calculated by summing the sub categories (general, physical, emotional and mental) and subtracting vigor. Total scores range from -24 to 96, with a higher score indicating more fatigue.
Time frame: week 4
Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 8
Fatigue symptoms will be measured using the 30-item Multidimensional Fatigue Symptom Inventory - Short Form, a validated measure that yields one overall score of total fatigue calculated using five sub scales (general, physical, emotional, mental, vigor). With the exception of the vigor sub scale, higher scores indicate greater fatigue. Total fatigue score is calculated by summing the sub categories (general, physical, emotional and mental) and subtracting vigor. Total scores range from -24 to 96, with a higher score indicating more fatigue.
Time frame: week 8