Role of Skeletal Muscle Nitric Oxide Production in Age-related Fatigue and Fatigability
Condition: Fatigue; Aging
MeSH terms: Fatigue
Study type: Interventional

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.
    

Intervention name(s): Placebo sildenafil; Sildenafil
Intervention type(s): Drug; Drug
Intervention description(s): Oral, daily, 1 week.; oral, 25mg, daily for 1 week
Other intervention name(s): Viagra; Viagra
Intervention MeSH terms: Sildenafil Citrate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: fatigue; aging