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PhD Program in Space Life Science Muscle Performance in Long-Term Spaceflight: Challenges Facing the U.S. Space Program Michael B. Reid, Ph.D. Department.

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Presentation on theme: "PhD Program in Space Life Science Muscle Performance in Long-Term Spaceflight: Challenges Facing the U.S. Space Program Michael B. Reid, Ph.D. Department."— Presentation transcript:

1 PhD Program in Space Life Science Muscle Performance in Long-Term Spaceflight: Challenges Facing the U.S. Space Program Michael B. Reid, Ph.D. Department of Physiology University of Kentucky Medical Center

2 PhD Program in Space Life Science NASA’s Mandate for the Future: Into The Cosmos “We do not know where this journey will end, yet we know this: Human beings are headed into the cosmos.” - President George W. Bush January, 2004

3 PhD Program in Space Life Science The NASA Response: Vision for the Future  The Vision for Space Exploration  Manned spaceflight  Complete the ISS by 2010  Return to the moon by 2020  Prepare for Mars mission Courtesy of NASA

4 PhD Program in Space Life Science The NASA Vision: Long-Duration Missions  NASA’s plans for long- duration missions 1. ISS 2. Establish as lunar base for technical development for equipment and instrumentation 3. Mars probes 4. Mars Courtesy of NASA Mars Probe Lunar Base Mars ISS

5 PhD Program in Space Life Science The NASA Concern: Maintaining Crew Health in Space  Aspects of long-term space flight  Harsh environment  Confined space  Life support issues  Adaptation to 0 Gz Courtesy of NASA

6 PhD Program in Space Life Science National Space Biomedical Research Institute (NSBRI)  Formed in 1997  NSBRI research seeks solutions to health concerns facing astronauts on long missions. Patients on Earth suffering from similar conditions will benefit from these advances.   12 consortium institutions  ~270 investigators  7 research areas including:  Cardiovascular Alterations  Human Factors and Performance  Musculoskeletal Alterations  Neurobehavioral and Psychosocial Factors  Radiation Effects  Sensorimotor Adaptation  Smart Medical Systems and Technology

7 PhD Program in Space Life Science Muscle Research in Microgravity Human Studies In Flight  Challenge: transport exercise equipment to ISS and keep it functioning  Treadmill  Cycle ergometer  Body mass measurement device  Standardized force used to measure inertial changes  Calculates changes in body mass while in orbit Body mass measurement device Treadmill Cycle ergometer Courtesy of NASA

8 PhD Program in Space Life Science Muscle Research in Microgravity Human Muscle Ultrastructure  Electron micrographs of longitudinal sections of slow muscle fibers obtained from soleus muscles of an astronaut before (A) and after (B) a 17-day spaceflight  Structural changes of post flight muscle fiber:  Skeletal structure  Z-line streaming  Loss of thin filaments  Increases accumulation of lipid droplets  Changes in mitochondrial morphology Reproduced from Fitts RH, et al. Physiology of a microgravity environment; invited review: microgravity and skeletal muscle. J Appl Physiol 89: , 2000.

9 PhD Program in Space Life Science Muscle Research in Microgravity: Human Muscle Endurance  Effect of space flight on limb muscle endurance in Sprague-Dawley rats  Muscle endurance is compromised 6 days after flight  Loss in muscle strength overtime Reproduced from Caiozzo V.J., et al. Effect of spaceflight on skeletal muscle: mechanical properties and myosin isoform content of a slow muscle. J Appl Physiol 76: , 1994.

10 PhD Program in Space Life Science Muscle Research in Microgravity: Human Muscle Weakness  Loss in muscle strength over time  Comparison of mean percent changes in planar and dorsal flexion isokinetic strengths (0-180°/s) between 110 (▲) and 237 (●) days of exposure to microgravity.  Progressive adaptation of microgravity differs depending on muscle groups Reproduced from Greenleaf JE, et al. Exercise-training protocols for astronauts in microgravity. J Appl Physiol 67: 2191–2204, 1989.

11 PhD Program in Space Life Science Muscle Research in Microgravity: Rodent Studies In Flight  Study of non-human species in space (i.e. rats)  Rodent chambers Unable to display images

12 PhD Program in Space Life Science Muscle Research in Microgravity: Fiber Atrophy in Rats vs. Men  Percent change in fiber cross-sectional area preflight compared with post flight for slow type I and fast II fibers from the rat soleus (Sol), medial gastrocnemius (MG), and tibialis anterior (TA) and from the human vastus lateralis (VL), Sol, and gastrocnemius Reproduced from Fitts, et al. J Appl Physiol 89: , 2000.

13 PhD Program in Space Life Science Muscle Research in Microgravity: Limitations of the Approach  Few subjects or animals available  Many restrictions on access  time restraints  cooperation  Technical limits in-flight  In-flight studies useful for proof-of- concept only, not systematic research. Courtesy of NASA

14 PhD Program in Space Life Science Ground-Based Research Models: The NASA KC-135 “Vomit Comet”  Ground-based model  Location: Ellington Field (Texas)  Used to make selected types of measurements Courtesy of NASA

15 PhD Program in Space Life Science Ground-Based Research Models: Limitations of the Vomit Comet  Flies over the Gulf of Mexico in a parabolic curve  20-sec exposures  Limited access  Nausea!  The diagram to the right shows a flight plan for the KC-135 during typical zero-g maneuvers Courtesy of NASA

16 PhD Program in Space Life Science Ground-Based Research Models: Bedrest Studies  Used to measure human response to countermeasures  Healthy volunteers  4-8 weeks or more in bed  Measure muscle function and learn how muscle is adapting Courtesy of NASA

17 PhD Program in Space Life Science Ground-Based Research Models: Exercise and Atrophy in Bedrest  Resistance exercise of volunteers in bed rest  Fiber diameter changes slowly over 60 days  Resistance exercise is protective against loss of muscle function  Graph to right: Quadriceps femoris cross sectional area (CSA) during bed rest for the right (filled symbols) and left (open symbols) leg, for RVE (n=9, triangles and solid line) and Ctrl (n=9, circles and dashed lines) Graph reproduced from Mulder, et al. Eur J Appl Physiol 97: , 2006

18 PhD Program in Space Life Science Ground-Based Research Models: Muscle Catabolism in Bedrest  MRI data, cross section of human thigh before and after bed rest  Muscles atrophy is seen clearly in a bed rest study Reprinted with permission of John Wiley & Sons, Inc. Ubiquitin ligase gene expression in healthy volunteers with 20-day bedrest. Muscle Nerve 34(4): , © 2006 Wiley Periodicals, Inc.

19 PhD Program in Space Life Science Ground-Based Research Models: Muscle Catabolism in Bedrest  Ubiquitin – molecular tag  Communicates with muscle to breakdown protein via 26S proteasome  High amounts of Ubiquitin after bed rest indicate more muscle protein that is tagged for breakdown/loss of muscle mass Reprinted with permission of John Wiley & Sons, Inc. Ubiquitin ligase gene expression in healthy volunteers with 20-day bedrest. Muscle Nerve 34(4): , © 2006 Wiley Periodicals, Inc.

20 PhD Program in Space Life Science Ground-Based Research Models: Muscle Catabolism in Bedrest  Changes in gene expression related to muscle metabolism  MuRf-1 and atrogin-1: muscle specific E3 proteins that target ubiquitin to proteins that will be degraded  Both are elevated in catabolic state (starvation) Reprinted with permission of John Wiley & Sons, Inc. Ubiquitin ligase gene expression in healthy volunteers with 20-day bedrest. Muscle Nerve 34(4): , © 2006 Wiley Periodicals, Inc.

21 PhD Program in Space Life Science Ground-Based Research Models: Limitations to Bedrest Studies  Subject recruitment  Expense  Logistics Courtesy of NASA

22 PhD Program in Space Life Science Ground-Based Research Models: Hindlimb Unloading in Rodents  Animal studies are used as an alternative to bedrest projects  Hindlimb suspension model used for conditioning antigravity muscles of rodents  Height of hindlimbs are adjusted and do not apply force to antigravity muscles  Rodent muscles adapt to conditions just as human muscles adapt in various models  Unloading induced muscle atrophy mimics microgravity

23 PhD Program in Space Life Science Ground-Based Research Models: Atrophy and Oxidative Stress in Unloaded Soleus  Oxidant dysregulation and atrophy in unloaded soleus muscle: time course of increases in oxidant activity (fluorescence emissions) and decreases in soleus weight (muscle weight) during 1–12 days of hindlimb unloading.  Rapid loss of muscle mass (day 1-2); rate of decline of muscle levels out around day 5-6 Graph reproduced from: Arbogast, et al., J Appl Physiol 102: , 2007.

24 PhD Program in Space Life Science  Measurement of free radical activity in cytoplasm of soleus cell  Cells have oxidant activity – reactive oxygen species (ROS), Nitric Oxide and its derivatives  Rapid increase in fluorescence indicates an increase in oxidant activity  Oxidant activity remains elevated during the entire atrophic activity during unloading  Rapid changes in oxidant activity and muscle mass are coincidental Ground-Based Research Models: Atrophy and Oxidative Stress in Unloaded Soleus Graph reproduced from: Arbogast, et al., J Appl Physiol 102: , 2007.

25 PhD Program in Space Life Science Ground-Based Research Models: Antioxidant Properties of Bowman-Birk Inhibitor Concentrate (BBIC)  BBIC is made from soybeans and is a serine protease inhibitor  Antioxidant effects  Control: no hindlimb unloading  Unloaded: increase in oxidant activity  Unloaded + BBIC: decrease in oxidant activity with BBIC Graphs reproduced from: Arbogast, et al., J Appl Physiol 102: , 2007.

26 PhD Program in Space Life Science  Superoxide reduces cytochrome c  BBIC cuts the signal in half – significant depression in superoxide activity. Graphs reproduced from: Arbogast, et al., J Appl Physiol 102: , Ground-Based Research Models: Antioxidant Properties of Bowman-Birk Inhibitor Concentrate (BBIC)

27 PhD Program in Space Life Science Ground-Based Research Models: BBIC Inhibits Atrophy and Weakness in Unloaded Soleus  3 days of conditioning  Unloaded mice fed BBIC had a drop in muscle cross section and muscle weight  BBIC preserves muscle mass in the absence of exercise training Graphs reproduced from: Arbogast, et al., J Appl Physiol 102: , 2007.

28 PhD Program in Space Life Science  Relative to control muscles, soleus force is depressed at stimulation frequencies of 50–300 Hz after unloading. BBIC supplementation partially prevents this decrement (unloaded + BBIC). Graphs reproduced from: Arbogast, et al., J Appl Physiol, 102: , Ground-Based Research Models: BBIC Inhibits Atrophy and Weakness in Unloaded Soleus

29 PhD Program in Space Life Science  Muscle fatigue occurs during Extravehicular Activity (EVAs)  Story Musgrave - longest serving astronaut  MS in Physiology, University of Kentucky  Focus: glove design and the problems associated with it Muscle Fatigue During EVA: Other Concerns at JSC JSC Story Musgrave Hubble Space Telescope Mission Control

30 PhD Program in Space Life Science Space Suit: Glove Design Courtesy of NASA  Pressurization stiffens glove  Finger dexterity is reduced  Causes hand and forearm fatigue  Can limit EVA performance

31 PhD Program in Space Life Science N-Acetylcysteine (NAC) as a Countermeasure: Isometric Handgrip Exercise  Experiment: Isometric handgrip exercise + Antioxidant N- Acetylcysteine (NAC) as a countermeasure  Evaluate astronauts ability to do work using an Ergometer  Measure changes in handgrip performance in crew members over time  Can we quantitate fatigue effectively?  Is NAC an effective countermeasure? Ergometer

32 PhD Program in Space Life Science N-Acetylcysteine (NAC) as a Countermeasure: Isometric Handgrip Exercise  Can we quantitate fatigue effectively? Yes  Is NAC an effective countermeasure? Yes  Matuszczak Y, Farid M, Jones J, Lansdowne S, Smith MA, Taylor AA, and Reid MB. Effects of N- acetylcysteine on gluatathione oxidation and fatigue during handgrip exercise. Muscle Nerve 32: , Ergometer

33 PhD Program in Space Life Science N-Acetylcysteine (NAC) as a Countermeasure: Isometric Handgrip Exercise  Oxidized glutathione measured in red blood cells – index of oxidative stress  Right hand exercise  Conclusion:  NAC prevents increase of oxidized glutathione during exercise and recovery  NAC works to preserve glutathione homeostasis and blunt oxidative stress

34 PhD Program in Space Life Science N-Acetylcysteine (NAC) as a Countermeasure: Isometric Handgrip Exercise  Successful handgrip repetitions  3 different control runs  3-7 days apart  Endurance increases with NAC

35 PhD Program in Space Life Science N-Acetylcysteine (NAC) as Countermeasure: Ongoing Research  Example of a flyer to attract volunteers to test if NAC capsules are a useful countermeasure for the astronaut core

36 PhD Program in Space Life Science Ground-Based Applications: Space Flight vs. Cachexia  Similarities between the clinical effects of space flight and cachexia among people on earth  Nutritional or pharmacological treatment is needed Mosby's dictionary of complementary and alternative medicine Author: Wayne B Jonas Publisher: Mosby, ©2005.

37 PhD Program in Space Life Science Similarities in Space Flight vs. Cachexia  Muscle atrophy  Regulated by ubiquitin conjugation  Contractile dysfunction  Loss in force / cross-section  Muscles are smaller and do not function as well  Oxidative stress  Mediated by reactive oxygen species (ROS) Mosby's dictionary of complementary and alternative medicine Author: Wayne B Jonas Publisher: Mosby, ©2005.

38 PhD Program in Space Life Science NAC as Clinical Therapy: Ongoing Research  Pilot study: heart failure patients  Test NAC in these patients to lessen fatigue that decreases mobility, quality of live, increases illness

39 PhD Program in Space Life Science Comment from the Audience Many heart failure patients have muscle weakness and it is one of the major problems in moving around. It is a systemic disease and involves muscle recovery.

40 PhD Program in Space Life Science Current Model: ROS as Mediators of Muscle Weakness  2 factors that act on a simplified muscle cell  Mechanical unloading and inflammatory cytokines to increase production of ROS  ROS alter gene expression, increase production of regulatory proteins and stimulate ubiquitin conjugation.  Protein loss – smaller muscles  Muscle weakness is the final result. Unable to display image of Astronaut Ed Lu being carried by the crowd because he is too weak to walk after he returns following 6 months on the ISS Mosby's dictionary of complementary and alternative medicine Author: Wayne B Jonas Publisher: Mosby, ©2005. Unable to display image

41 PhD Program in Space Life Science NSBRI Muscle Team Long-Term Goal: Countermeasures Effective in Space and on Earth  NSBRI’s goal:  Earth based benefits for people with chronic disease plus astronauts Mosby's dictionary of complementary and alternative medicine Author: Wayne B Jonas Publisher: Mosby, ©2005. Courtesy of NASA

42 PhD Program in Space Life Science Acknowledgments Supported by the National Institutes of Health & National Space Biomedical Research Institute


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