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Redox Modulation of Skeletal Muscle Function in Microgravity

Principal Investigator:
Michael B. Reid, Ph.D.

University of Kentucky Medical Center

One of the risks associated with long-duration space missions is decreased skeletal muscle function. Lack of weight-bearing activity in microgravity leads to loss of muscle mass and problems with muscle contractions. In select situations like extravehicular activity, muscle fatigue could limit performance. When muscles do not bear weight, a loss of oxidant regulation occurs that contributes to atrophy and decreased function. In this study, Dr. Michael B. Reid seeks to define the loss of oxidant regulation and determine the time course, composition and the source of increased oxidant activity in non weight-bearing muscle. He will then evaluate selected antioxidants for their success in neutralizing and/or preventing muscle weakness and fatigue.

NASA Taskbook Entry

Technical Summary

NASA identifies loss of skeletal muscle function as a key concern for long-term missions. Gravitational unloading causes weakness of antigravity muscles due to loss of muscle mass (atrophy) and contractile dysfunction. In selected conditions, especially extravehicular activity (EVA), performance can also be limited by muscle fatigue. This project evaluated selected compounds, nutritional supplements and pharmacologic agents that may oppose oxidative stress in muscle and protect against weakness and fatigue. The experimental approach was designed to identify and develop countermeasures for human testing in the near-to-mid term. Experiments defined the loss of oxidant regulation that occurs with muscle unloading. Subsequent studies evaluated compounds for protective effects on muscle function. The efficacy of each compound tested in this project is supported by preliminary data from animal studies, human trials or both. Each compound is approved for systemic administration to humans.

Specific Aims

  1. To determine the time course, composition and source of increased oxidant activity in unloaded muscle. Experiments used mice conditioned by hindlimb unloading for up to two weeks. The antigravity muscle soleus was studied to define the time course of oxidant dysregulation after unloading, to determine the relative contributions of reactive oxygen species versus nitric oxide derivatives, and to test mitochondria as the primary source of increased oxidant activity.
  2. To evaluate selected antioxidants as countermeasures for weakness in unloaded muscle. In these experiments, mice conditioned by hindlimb unloading were treated with one of four interventions that oppose oxidant activity or oxidant-mediated signaling: allopurinol (xanthine oxidase inhibitor), curcumin (NF-kappaB inhibitor), Bowman-Birk inhibitor complex (protease inhibitor), or N-acetylcysteine (NAC; reduced thiol donor). Unloaded soleus was tested for protection against oxidative stress, contractile dysfunction and muscle atrophy.
  3. To test NAC as a countermeasure for handgrip fatigue in humans. Experiments in healthy volunteers defined the appropriate preparation (solution versus capsule) and dosage for oral NAC administration and tested NAC effects on handgrip strength and handgrip fatigue during concentric exercise.

Earth Applications

This research directly addresses two Earth-based problems, loss of function in unloaded muscle and muscle fatigue. The first problem occurs in individuals who are immobilized by injury or surgery. Muscles of the affected limbs atrophy and weaken, making it difficult for the individual to return to normal daily activity. The resulting inactivity lessens the quality of life, increases hospitalization and therapeutic costs, and increases the likelihood of pneumonia, venous thromboses and other serious medical complications. A practical countermeasure to lessen atrophy and weakness would directly benefit these individuals, lessening the problems caused by transient immobilization.

The second problem is familiar to us all. Acute muscle fatigue is a common feature of strenuous exercise. A countermeasure to inhibit fatigue would benefit a broad range of the U.S. populace whose work requires physical exertion ranging from military professionals and firefighters, to police officers and construction workers. The implications for professional athletes are all too obvious.

This project's funding ended in 2009