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Principal Investigator:
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Michael B. Reid, Ph.D.
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Organization:
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University of Kentucky Medical Center
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Project Ended:
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2005
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Weightlessness is primarily held responsible for muscle atrophy and fatigue in space.
Dr. Michael B. Reid is examining the role of oxygen-centered radicals and radiation as possible mediators of these processes. Dr. Reid is also evaluating antioxidant supplements as possible interventions to inhibit atrophy and fatigue.
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Principal Investigator:
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Michael B. Reid, Ph.D.
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Organization:
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University of Kentucky Medical Center
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Project Ended:
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2005
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Exercise-induced fatigue and muscle atrophy are mediated in part by reactive oxygen species (ROS), a stimulus that may be exaggerated by radiation during spaceflight. The project assessed the roles of ROS signaling and radiation on muscle fatigue and atrophy and is testing antioxidants as possible countermeasures. Progress was hindered by severe damage to our institution by Tropical Storm Allison in June, 2001. These losses were resolved and we have made rapid progress on the project over the last year as outlined below.
Specific Aims
- To determine if oxidative stress contributes to muscle fatigue during handgrip exercise. Fatigue of hand and forearm muscles may limit crew performance during extravehicular activity (EVA). N-acetylcysteine (NAC) is an antioxidant that inhibits muscle fatigue in humans. We have recently completed experiments testing the capacity of NAC to inhibit muscle fatigue and oxidative stress in humans during handgrip exercise. Working with Dr. Jeff Jones, Flight Surgeon at NASA Johnson Space Center, we used equipment and test procedures designed for use on the International Space Station. Results of the study show the feasibility of this approach. NAC abolished glutathione oxidation blood draining the affected muscle groups and increased handgrip endurance by 30% relative to untreated trials. This aim has been completed. Follow-up studies are being planned that will test the importance of these findings in a more operationally-relevant setting.
- To determine whether ionizing radiation accelerates ROS production and fatigue in skeletal muscle. We postulated that proton radiation absorbed during EVA would increase tissue ROS levels and accelerate muscle fatigue. We were testing this postulate in collaboration with Dr. Carlos Gonzalez, Director of the cyclotron at the University of Texas Medical School, when Tropical Storm Allison destroyed the cyclotron facility in 2001. The facility has not been rebuilt. Resources intended for these experiments have been redirected to studies of mechanisms regulating muscle atrophy and to tests of potential countermeasures (Aim 3).
- To evaluate oxidative stress as a mediator of muscle weakness caused by gravitational unloading. Muscle atrophy and contractile dysfunction cause weakness after prolonged spaceflight. We are evaluating oxidative stress as a cause of these changes in mouse soleus during 12-days of hindlimb unloading and are using cell culture techniques to evaluate mechanism. Our results show that: 1.) unloading increases oxidant activity within soleus muscle fibers; 2.) contractile dysfunction is blunted by administration of some antioxidants (NAC, allopurinol) but not others (curcumin, vitamin E); 3.) a novel ubiquitin conjugating enzyme, UbcH2/E220k, is highly expressed in skeletal muscle, is upregulated by ROS exposure, and mediates ubiquitin conjugation to muscle proteins; 4.) hydrogen peroxide upregulates expression of atrogin1/MAFbx, a key ubiquitin ligase that regulates muscle atrophy; 5.) this signal is transduced by p38 MAP kinase; and 6.) p38 inhibition blocks atrogin1/MAFbx upregulation and the associated rise in ubiquitin conjugating activity. We are testing the roles of these transcriptional mechanisms in atrophy of unloaded muscle and will continue to evaluate potential countermeasures.
- To determine if radiation stimulates atrophic signaling in muscle. We postulated that radiation-derived ROS might stimulate catabolic signaling and planned to measure activity of redox-sensitive pathways in muscle after proton irradiation. Destruction of the Medical Center cyclotron has prevented these experiments. Project resources have been redirected to studies of cellular mechanism and putative countermeasures (Aim 3).
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Principal Investigator:
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Michael B. Reid, Ph.D.
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Organization:
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University of Kentucky Medical Center
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Project Ended:
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2005
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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.
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