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

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.