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Project Title:  Redox Modulation of Skeletal Muscle Function in Microgravity Reduce
Fiscal Year: FY 2009 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 08/31/2009  
Task Last Updated: 05/12/2010 
Download report in PDF pdf
Principal Investigator/Affiliation:   Reid, Michael B. Ph.D. / University of Kentucky 
Address:  800 Rose Street, Room MS-509 
 
Lexington , KY 40536-0298 
Email: michael.reid@uky.edu 
Phone: 859-323-6045  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Kentucky 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Jones, Jeffrey  NASA JSC 
Kennedy, Ann  University of Pennsylvania 
Sabet, Arman  University of Kentucky 
Project Information: Grant/Contract No. NCC 9-58-MA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 NSBRI NNH04ZUU003N Human Health in Space 
Grant/Contract No.: NCC 9-58-MA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Muscle:Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance
(2) Nutrition:Risk of Inadequate Nutrition
Human Research Program Gaps: (1) M23:Determine if factors other than unloading contribute to muscle atrophy during space flight (IRP Rev F)
Task Description: NASA's Critical Path Roadmap 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. The current project evaluates selected compounds, nutritional supplements and pharmacologic agents, that may oppose oxidative stress in muscle and protect against weakness and fatigue. The experimental approach is designed to identify and develop countermeasures for human testing in the near-to-mid term. Initial experiments will define the loss of oxidant regulation that occurs with muscle unloading. Subsequent studies will evaluate 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. Experiments will address three specific aims:

Aim 1. To determine the time course, composition, and source of increased oxidant activity in unloaded muscle. Experiments will use mice conditioned by hindlimb unloading for up to two weeks. The antigravity muscle soleus will be studied to define the time course of oxidant dysregulation after unloading, to determine the relative contributions of reactive oxygen species vs. nitric oxide derivatives, and to test mitochondria as the primary source of increased oxidant activity.

Aim 2. To evaluate selected antioxidants as countermeasures for weakness in unloaded muscle. In these experiments, mice conditioned by hindlimb unloading will be 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 will be tested for protection against oxidative stress, contractile dysfunction, and muscle atrophy.

Aim 3. To test NAC as a countermeasure for handgrip fatigue in humans. Experiments in healthy volunteers will define the appropriate preparation (solution vs. capsule) and dosage for oral NAC administration and will test NAC effects on handgrip strength and handgrip fatigue during concentric exercise.

Research Impact/Earth Benefits: 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 US populace whose work requires physical exertion ranging from military professionals to firefighters, from police officers to construction workers. The implications for professional athletes are all too obvious.

Task Progress & Bibliography Information FY2009 
Task Progress: Our project is designed to address three sets of tasks, re-phrased from specific aims. Our progress over the previous year is summarized below:

Task 1. To determine the time course, composition, and source of increased oxidant activity in unloaded muscle. Experiments use mice conditioned by hindlimb unloading for up to three weeks. The antigravity muscle soleus was excised for functional and biochemical assays to assess changes in oxidant regulation. Experiments to address Task 1 are complete. Related studies of muscle gene expression during acute gravitational unloading were also completed this year. Homologous studies of gene expression in unloaded bone are in progress.

Task 2. To test selected antioxidants as possible countermeasures for weakness of unloaded muscle. Mice conditioned by hindlimb unloading were treated with compounds that oppose oxidant-mediated signaling via four distinct mechanisms: allopurinol, curcumin, Bowman-Birk inhibitor complex, or N-acetylcysteine (NAC). Soleus muscle atrophy and contractile function were monitored to assess countermeasure efficacy. Experiments to address Task 2 are complete.

Task 3. To evaluate NAC as a countermeasure for handgrip fatigue in humans. We previously showed that NAC inhibits human muscle fatigue. A final series of experiments in healthy volunteers have optimized the preparation and dosage of oral NAC administration for use in future countermeasure testing. A related study has identified the antioxidant OTC as a promising anti-fatigue agent and an alternative to NAC.

Bibliography Type: Description: (Last Updated: 08/24/2020) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Ferreira LF, Gilliam LA, Reid MB. "L-2-Oxothiazolidine-4-carboxylate reverses glutathione oxidation and delays fatigue of skeletal muscle in vitro." J Appl Physiol. 2009 Jul;107(1):211-6. PMID: 19407260 , Jul-2009
Articles in Peer-reviewed Journals Reid MB. "Reactive oxygen species as agents of fatigue." Med Sci Sports Exerc. 2016 Nov;48(11):2239-46. https://doi.org/10.1249/MSS.0000000000001006 ; PMID: 27285492 , Nov-2016
Project Title:  Redox Modulation of Skeletal Muscle Function in Microgravity Reduce
Fiscal Year: FY 2008 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 08/31/2009  
Task Last Updated: 10/07/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Reid, Michael B. Ph.D. / University of Kentucky 
Address:  800 Rose Street, Room MS-509 
 
Lexington , KY 40536-0298 
Email: michael.reid@uky.edu 
Phone: 859-323-6045  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Kentucky 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Jones, Jeffrey  NASA JSC 
Kennedy, Ann  University of Pennsylvania 
Sabet, Arman  University of Kentucky 
Project Information: Grant/Contract No. NCC 9-58-MA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 NSBRI NNH04ZUU003N Human Health in Space 
Grant/Contract No.: NCC 9-58-MA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Muscle:Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance
(2) Nutrition:Risk of Inadequate Nutrition
Human Research Program Gaps: (1) M23:Determine if factors other than unloading contribute to muscle atrophy during space flight (IRP Rev F)
Task Description: NASA’s Critical Path Roadmap 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. The current project evaluates selected compounds, nutritional supplements and pharmacologic agents, that may oppose oxidative stress in muscle and protect against weakness and fatigue. The experimental approach is designed to identify and develop countermeasures for human testing in the near-to-mid term. Initial experiments will define the loss of oxidant regulation that occurs with muscle unloading. Subsequent studies will evaluate 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.

Experiments will address three specific aims:

Aim 1. To determine the time course, composition, and source of increased oxidant activity in unloaded muscle. Experiments will use mice conditioned by hindlimb unloading for up to two weeks. The antigravity muscle soleus will be studied to define the time course of oxidant dysregulation after unloading, to determine the relative contributions of reactive oxygen species vs. nitric oxide derivatives, and to test mitochondria as the primary source of increased oxidant activity.

Aim 2. To evaluate selected antioxidants as countermeasures for weakness in unloaded muscle. In these experiments, mice conditioned by hindlimb unloading will be 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 will be tested for protection against oxidative stress, contractile dysfunction, and muscle atrophy.

Aim 3. To test NAC as a countermeasure for handgrip fatigue in humans. Experiments in healthy volunteers will define the appropriate preparation (solution vs. capsule) and dosage for oral NAC administration and will test NAC effects on handgrip strength and handgrip fatigue during concentric exercise.

Research Impact/Earth Benefits: 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 US populace whose work requires physical exertion ranging from military professionals to firefighters, from police officers to construction workers. The implications for professional athletes are all too obvious.

Task Progress & Bibliography Information FY2008 
Task Progress: Our project is designed to address three sets of tasks, re-phrased from specific aims. Our progress over the previous year is summarized below:

Task 1. To determine the time course, composition, and source of increased oxidant activity in unloaded muscle. Experiments use mice conditioned by hindlimb unloading for up to three weeks. The antigravity muscle soleus was excised for functional and biochemical assays to assess changes in oxidant regulation. Experiments to address Task 1 are complete. Related studies of muscle gene expression during acute gravitational unloading were also completed this year. Homologous studies of gene expression in unloaded bone are in progress.

Task 2. To test selected antioxidants as possible countermeasures for weakness of unloaded muscle. Mice conditioned by hindlimb unloading were treated with compounds that oppose oxidant-mediated signaling via four distinct mechanisms: allopurinol, curcumin, Bowman-Birk inhibitor complex, or N-acetylcysteine (NAC). Soleus muscle atrophy and contractile function were monitored to assess countermeasure efficacy. Experiments to address Task 2 are complete. Collaborative plans to extend this work by testing additional nutritional compounds have stalled this year due to shifts in corporate priorities at Unilever.

Task 3. To evaluate NAC as a countermeasure for handgrip fatigue in humans. NAC has been shown to inhibit human muscle fatigue in a variety of published reports. Experiments in healthy volunteers will optimize the preparation and dosage of oral NAC administration and will test NAC effects on handgrip strength and handgrip fatigue during concentric exercise. Experiments to address Task 3 are in progress. A related study of the antioxidant OTC as an anti-fatigue agent is also in progress. Both studies will be completed in the coming year.

Bibliography Type: Description: (Last Updated: 08/24/2020) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Ferreira LF, Reid MB. "Muscle-derived ROS and thiol regulation in muscle fatigue." J Appl Physiol. 2008 Mar;104(3):853-60. PMID: 18006866 , Mar-2008
Articles in Peer-reviewed Journals Reid MB. "Free radicals and muscle fatigue: of ROS, canaries, and the IOC." Free Radic Biol Med. 2008 Jan 15;44(2):169-79. PMID: 18191753 , Jan-2008
Project Title:  Redox Modulation of Skeletal Muscle Function in Microgravity Reduce
Fiscal Year: FY 2007 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 08/31/2009  
Task Last Updated: 02/01/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Reid, Michael B. Ph.D. / University of Kentucky 
Address:  800 Rose Street, Room MS-509 
 
Lexington , KY 40536-0298 
Email: michael.reid@uky.edu 
Phone: 859-323-6045  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Kentucky 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Jones, Jeffrey  NASA JSC 
Kennedy, Ann  University of Pennsylvania 
Sabet, Arman  University of Kentucky 
Project Information: Grant/Contract No. NCC 9-58-MA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 NSBRI NNH04ZUU003N Human Health in Space 
Grant/Contract No.: NCC 9-58-MA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Muscle:Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance
(2) Nutrition:Risk of Inadequate Nutrition
Human Research Program Gaps: (1) M23:Determine if factors other than unloading contribute to muscle atrophy during space flight (IRP Rev F)
Task Description: NASA’s Critical Path Roadmap 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. The current project evaluates selected compounds, nutritional supplements and pharmacologic agents, that may oppose oxidative stress in muscle and protect against weakness and fatigue. The experimental approach is designed to identify and develop countermeasures for human testing in the near-to-mid term. Initial experiments will define the loss of oxidant regulation that occurs with muscle unloading. Subsequent studies will evaluate 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.

Experiments will address three specific aims:

Aim 1. To determine the time course, composition, and source of increased oxidant activity in unloaded muscle. Experiments will use mice conditioned by hindlimb unloading for up to two weeks. The antigravity muscle soleus will be studied to define the time course of oxidant dysregulation after unloading, to determine the relative contributions of reactive oxygen species vs. nitric oxide derivatives, and to test mitochondria as the primary source of increased oxidant activity.

Aim 2. To evaluate selected antioxidants as countermeasures for weakness in unloaded muscle. In these experiments, mice conditioned by hindlimb unloading will be 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 will be tested for protection against oxidative stress, contractile dysfunction, and muscle atrophy.

Aim 3. To test NAC as a countermeasure for handgrip fatigue in humans. Experiments in healthy volunteers will define the appropriate preparation (solution vs. capsule) and dosage for oral NAC administration and will test NAC effects on handgrip strength and handgrip fatigue during concentric exercise.

Research Impact/Earth Benefits: 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 US populace whose work requires physical exertion ranging from military professionals to firefighters, from police officers to construction workers. The implications for professional athletes are all too obvious.

Task Progress & Bibliography Information FY2007 
Task Progress: Our project is designed to address three sets of tasks, also known as specific aims. Our progress on each of these tasks over the previous year is summarized below:

Task 1. Experiments originally proposed for Aim 1 are complete. We are extending this line of research by a new series of studies that test for changes in muscle and bone gene expression during gravitational unloading. DNA microarray techniques are being used to screen for genes that regulate muscle and bone growth, catabolism, and redox homeostasis. We seek novel markers of tissue adaptation and new targets for therapeutic intervention.

Task 2. Our most recent study tested Bowman-Birk inhibitor complex (BBIC), a soybean-derived nutritional supplement, for effects on unloaded muscle. Soleus muscles of mice fed BBIC exhibited lower intracellular oxidant activity, less atrophy, and a smaller decrement in specific force. These data confirm previous findings by other investigators that BBIC protects unloaded muscle in mice and provide the first direct evidence that BBIC has antioxidant properties. In combination, the available data identify BBIC as an attractive compound for future tests in humans, i.e., during bedrest. Experiments proposed for original Aim 2 are now complete. To extend this work, we have begun collaborations with Unilever, a major international corporation in the field of food products and nutrition. We are working with scientists at Unilever to test novel nutritional interventions that may preserve muscle and bone during unloading.

Task 3. Our progress on Aim 3 has been hampered by the unexpected departures of two key personnel. Our study coordinator and medical advisor each left Kentucky for positions outside the state. We have subsequently recruited outstanding replacements. Dr. Leonardo Ferreira, a postdoctoral fellow trained in redox biology and muscle metabolism, is the new study coordinator. Our new medical advisor is Dr. Leigh Ann Callahan, a board certified subspecialist in pulmonary and critical care medicine. Both individuals have completed human studies training and are approved by the IRB to participate in our protocol. Dr. Ferreira is fully trained in use of the ergometer system and data collection software. He is now recruiting and training subjects to participate in NAC studies. Despite these considerable delays, we retain our original goal of completing all three study arms during the final year of the project.

Bibliography Type: Description: (Last Updated: 08/24/2020) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Arbogast S, Smith J, Matuszczak Y, Hardin BJ, Moylan JS, Smith JD, Ware J, Kennedy AR, Reid MB. "Bowman-Birk inhibitor concentrate prevents atrophy, weakness and oxidative stress in soleus muscle of hindlimb-unloaded mice." J Appl Physiol. 2007 Mar;102(3):956-64. PMID: 17110517 , Mar-2007
Articles in Peer-reviewed Journals Reid MB. "Free radicals and muscle fatigue: of ROS, canaries, and the IOC." Free Radic Biol Med. Epub 2007 Mar 12. Review. PMID: 18191753 , Mar-2007
Articles in Peer-reviewed Journals Farid M, Reid MB, Li Y-P, Gerken E, Durham WJ. "Effects of dietary curcumin or N-acetylcysteine on NF-kappaB activity and contractile performance in ambulatory and unloaded murine soleus." Nutr Metab (Lond). 2005 Aug 26;2:20. PMID: 16124875 , Aug-2005
Books/Book Chapters Moylan JS, Durham WJ, Reid MB. "Muscle, oxidative stress, and aging." in "Oxidative stress, exercise, and aging." Ed. H.M. Alessio, A.E. Hagerman. London : Imperial College Press, 2006, p. 109-124., Mar-2006
Project Title:  Redox Modulation of Skeletal Muscle Function in Microgravity Reduce
Fiscal Year: FY 2006 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 08/31/2009  
Task Last Updated: 01/08/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Reid, Michael B. Ph.D. / University of Kentucky 
Address:  800 Rose Street, Room MS-509 
 
Lexington , KY 40536-0298 
Email: michael.reid@uky.edu 
Phone: 859-323-6045  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Kentucky 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Jones, Jeffrey  NASA JSC 
Kennedy, Ann  University of Pennsylvania 
Sabet, Arman  University of Kentucky 
Project Information: Grant/Contract No. NCC 9-58-MA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: NSBRI 
Grant/Contract No.: NCC 9-58-MA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Muscle:Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance
(2) Nutrition:Risk of Inadequate Nutrition
Human Research Program Gaps: (1) M23:Determine if factors other than unloading contribute to muscle atrophy during space flight (IRP Rev F)
Task Description: NASA’s Critical Path Roadmap 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. The current project evaluates selected compounds, nutritional supplements and pharmacologic agents, that may oppose oxidative stress in muscle and protect against weakness and fatigue. The experimental approach is designed to identify and develop countermeasures for human testing in the near-to-mid term. Initial experiments will define the loss of oxidant regulation that occurs with muscle unloading. Subsequent studies will evaluate 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. Experiments will address three specific aims: Aim 1. To determine the time course, composition, and source of increased oxidant activity in unloaded muscle. Experiments will use mice conditioned by hindlimb unloading for up to two weeks. The antigravity muscle soleus will be studied to define the time course of oxidant dysregulation after unloading, to determine the relative contributions of reactive oxygen species vs. nitric oxide derivatives, and to test mitochondria as the primary source of increased oxidant activity. Aim 2. To evaluate selected antioxidants as countermeasures for weakness in unloaded muscle. In these experiments, mice conditioned by hindlimb unloading will be 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 will be tested for protection against oxidative stress, contractile dysfunction, and muscle atrophy. Aim 3. To test NAC as a countermeasure for handgrip fatigue in humans. Experiments in healthy volunteers will define the appropriate preparation (solution vs. capsule) and dosage for oral NAC administration and will test NAC effects on handgrip strength and handgrip fatigue during concentric exercise.

Research Impact/Earth Benefits: 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 US populace whose work requires physical exertion ranging from military professionals to firefighters, from police officers to construction workers. [The implications for professional athletes are all too obvious.]

Task Progress & Bibliography Information FY2006 
Task Progress: Our project is designed to address three sets of tasks, also known as specific aims. Our progress on each of these tasks is as follows:

1. To determine the time course, composition, and source of increased oxidant activity in unloaded muscle. Our experiments use mice conditioned by hindlimb unloading for up to three weeks. The antigravity muscle soleus is tested using functional and biochemical assays to determine any changes in free radical regulation by the muscle. Data from the previous year show that soleus muscles respond to hindlimb unloading by increasing the activity of NF-kappaB, a signaling molecule that promotes muscle atrophy. Also, soleus muscle mass decreases 43% after 10 days of unloading. This atrophy is biphasic, occurring rapidly over the first 3 days and then more slowly. Free radical activity in the muscle shows the opposite response, increasing during the first three days and then leveling off. These data suggest free radicals stimulate wasting of unloaded muscles.

2. To test selected antioxidants as possible countermeasures for weakness of unloaded muscle. Mice conditioned by hindlimb unloading are being treated with compounds that inhibit free radical activity. These include curcumin, N-acetylcysteine (NAC), allopurinol, and Bowman-Birk inhibitor concentrate (BBIC). Soleus muscle atrophy and contractile function are measured to determine the effectiveness of these possible countermeasures. We have found that antioxidant countermeasures vary in their effectiveness. Dietary supplementation with curcumin or NAC caused biochemical changes in the muscles that appeared promising. But the overall effects of these two compounds was unremarkable. Neither inhibited muscle atrophy or improved muscle function during unloading. In contrast, oral administration of allopurinol was protective. This compound lessened the weakness caused by muscle unloading despite the fact that muscle atrophy still occurred.

3. To evaluate NAC as a countermeasure for handgrip fatigue in humans. NAC has been shown to inhibit human muscle fatigue in several recent studies. Experiments in healthy volunteers are optimizing the preparation and dosage of oral NAC administration used to delay muscle fatigue during handgrip exercise. In the past year, we recruited a study coordinator and created a specially-designed device (‘ergometer’) to measure handgrip fatigue. The new ergometer overcomes several limitations of an earlier machine used in our previous research studies. We hope the new ergometer will provide more reliable measurements. We are now conducting dose-response studies of NAC capsules administered orally. To date we have screened 11 volunteers. Eight were unable to perform our fatiguing exercise protocol reproducibily and have been excused from the study. Three individuals have successfully completed the entire protocol and their blood samples are currently being analyzed to determine NAC effects.

Bibliography Type: Description: (Last Updated: 08/24/2020) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Matuszczak Y, Farid M, Jones J, Lansdowne S, Smith MA, Taylor AA, Reid MB. "Effects of N-acetylcysteine on glutathione oxidation and fatigue during handgrip exercise." Muscle Nerve. 2005 Nov;32(5):633-8. PMID: 16025522 , Nov-2005
Articles in Peer-reviewed Journals Reid MB. "Response of the ubiquitin-proteasome pathway to changes in muscle activity." Am J Physiol Regul Integr Comp Physiol. 2005 Jun;288(6):R1423-31. Review. PMID: 15886351 , Jun-2005
Articles in Peer-reviewed Journals Smith MA, Reid MB. "Redox modulation of contractile function in respiratory and limb skeletal muscle." Respir Physiol Neurobiol. 2006 Apr 28;151(2-3):229-41. Epub 2006 Feb 14. Review. PMID: 16481226 , Apr-2006
Awards Reid MB. "Citation for Distinguished Service, American Physiological Society (MB Reid)." Jan-2006
Awards Reid MB. "Distinguished Service Award, College of Health Sciences, University of Kentucky (MB Reid)." Jan-2006
Awards Reid MB. "Mentor Recognition Award, Clinical and Translational Science Conference, University of Kentucky (MB Reid)." Jan-2006
Project Title:  Redox Modulation of Skeletal Muscle Function in Microgravity Reduce
Fiscal Year: FY 2005 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 08/31/2009  
Task Last Updated: 12/03/2010 
Download report in PDF pdf
Principal Investigator/Affiliation:   Reid, Michael B. Ph.D. / University of Kentucky 
Address:  800 Rose Street, Room MS-509 
 
Lexington , KY 40536-0298 
Email: michael.reid@uky.edu 
Phone: 859-323-6045  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Kentucky 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Jones, Jeffrey  NASA JSC 
Kennedy, Ann  University of Pennsylvania 
Sabet, Arman  University of Kentucky 
Project Information: Grant/Contract No. NCC 9-58-MA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 NSBRI NNH04ZUU003N Human Health in Space 
Grant/Contract No.: NCC 9-58-MA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Muscle:Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance
(2) Nutrition:Risk of Inadequate Nutrition
Human Research Program Gaps: (1) M23:Determine if factors other than unloading contribute to muscle atrophy during space flight (IRP Rev F)
Task Description: NASA's Critical Path Roadmap 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. The current project evaluates selected compounds, nutritional supplements and pharmacologic agents, that may oppose oxidative stress in muscle and protect against weakness and fatigue. The experimental approach is designed to identify and develop countermeasures for human testing in the near-to-mid term. Initial experiments will define the loss of oxidant regulation that occurs with muscle unloading. Subsequent studies will evaluate 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. Experiments will address three specific aims:

Aim 1. To determine the time course, composition, and source of increased oxidant activity in unloaded muscle. Experiments will use mice conditioned by hindlimb unloading for up to two weeks. The antigravity muscle soleus will be studied to define the time course of oxidant dysregulation after unloading, to determine the relative contributions of reactive oxygen species vs. nitric oxide derivatives, and to test mitochondria as the primary source of increased oxidant activity.

Aim 2. To evaluate selected antioxidants as countermeasures for weakness in unloaded muscle. In these experiments, mice conditioned by hindlimb unloading will be 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 will be tested for protection against oxidative stress, contractile dysfunction, and muscle atrophy.

Aim 3. To test NAC as a countermeasure for handgrip fatigue in humans. Experiments in healthy volunteers will define the appropriate preparation (solution vs. capsule) and dosage for oral NAC administration and will test NAC effects on handgrip strength and handgrip fatigue during concentric exercise.

Research Impact/Earth Benefits: 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 US populace whose work requires physical exertion ranging from military professionals to firefighters, from police officers to construction workers. The implications for professional athletes are all too obvious.

Task Progress & Bibliography Information FY2005 
Task Progress: New project for FY2005.

[Ed. note: FY2005 record created in December 2010 when discovered missing; needed for statistical purposes]

Bibliography Type: Description: (Last Updated: 08/24/2020) 

Show Cumulative Bibliography Listing
 
 None in FY 2005