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Musculoskeletal Changes During Long Duration Spaceflight

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Musculoskeletal Changes During Long Duration Spaceflight Musculoskeletal changes during long duration spaceflight UW Peter R. Cavanagh Orthopaedics DISCLOSURES Peter Cavanagh has received grants from NASA and the National Space Biomedical Research Institute. He is a member of the Standing Review Board for the Space Shuttle and the International Space Station Program. Download PDF of this presentation and a list of references will be available tomorrow at: http://bit.ly/ksbQl or send Email request to: [email protected] ©2011 Peter R. Cavanagh Featured Science Brian Davis Kerim Genc Andrea Hansen Rodger Kram PhD PSU 1990 MS PSU 2003 Post-doc MS PSU 1986 MS CWRU 2009 UW 2009-11 PhD CWRU 2011 Exercise equipment Bone Loading Remote Monitoring Locomotion ©2011 Peter R. Cavanagh Our First Venture into Space Studies ACSMs Virtual Museum ©2011 Peter R. Cavanagh ©2011 Peter R. Cavanagh Hip-Knee Angle-Angle diagrams STS-7 and STS-8 (1983) Thornton et al. 1997 ©2011 Peter R. Cavanagh Outline MUSCLE Alterations with Spaceflight Mechanisms Countermeasures BONE Alterations with Spaceflight Mechanisms Countermeasures Future of Life Science Research in Space ©2011 Peter R. Cavanagh What is Long-duration? Mission Durations 1000 900 800 600 400 438 Mars 199 200 187 141 Duration in Days in Duration 84 0 2 18 1960 1980 2000 2020 2040 YEAR SkylabShuttleMirISS 4 ©2011 Peter R. Cavanagh ExpMirSTS1 EO11 ––STSExp – LD2 8020 Time Accumulated by Repeat Fliers 1000 6 5 3 2 5 3 4 4 2 4 Number of Flights 803 769 800 747 678 651 585 555 553 600 541 514 400 200 Lifetime days in Space in days Lifetime 0 Peggy Whitson #20 376.7 days Michael Fincke #26 365.9 days ©2011 Peter R. Cavanagh •Fitts RH, Trappe SW, Costill DL, Gallagher PM, Creer AC, Colloton PA, Peters JR, Romatowski JG, Bain JL, Riley DA. Prolonged space flight-induced alterations in the structure and function of human skeletal muscle fibres. J Physiol. 2010 Sep 15;588(Pt 18):3 MUSCLE: Alterations with Spaceflight Fitts RH, Trappe SW, Costill DL, Gallagher PM, Creer AC, Colloton PA, Peters JR, Romatowski JG, Bain JL, Riley DA. Prolonged space flight- induced alterations in the structure and function of human skeletal muscle fibres. J Physiol. 2010 Sep 15;588(Pt 18):3567-92. Trappe S, Costill D, Gallagher P, Creer A, Peters JR, Evans H, Riley DA, Fitts RH. Exercise in space: human skeletal muscle after 6 months aboard the International Space Station. J Appl Physiol. 2009 Apr;106(4):1159-68. Epub 2009 Jan 15. PMID: 19150852 Adams GR, Caiozzo VJ, Baldwin KM. Skeletal muscle unweighting: spaceflight and ground-based models. J Appl Physiol. 2003 Dec;95(6):2185-201. Review. PMID 14600160 ©2011 Peter R. Cavanagh MUSCLE : Mechanisms for Alterations • Fiber Type: Type 1 > loss/conversion • Fiber Type: Type 2 more preserved • Change in protein synthesis • Activation of ubiquitin-dependent proteolytic pathway (Ikemoto et al. 2001) • Impaired ability to replace or repair degraded contractile proteins (Kortebein et al. 2007). ©2011 Peter R. Cavanagh MUSCLE : Countermeasures Flywheel ARED iRED Exercise equipment ©2011 Peter R. Cavanagh Virginia•Xiaolan Ferguson, Zhou, Rachel Jin Lin Paietta,Wang, JohnLouis Lu, Stodieck, Yanping Song,Andrea Keith M. S.Hanson, Kwak, Qingsheng Mary H. Young, Jiao, Robert Ted Bateman, Rosenfeld, Michael Qing Chen, Lemus,Paul Thomas Boone,Kostenuik, W. Scott Eric Simonet,Jiao, David L. Lacey, Alfred L. Goldberg and H.Q. Han,Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Anta MUSCLE : Phamacological Countermeasures Myostatin inhibition Zhou et al. 2010 Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival. ©2011 Peter R. Cavanagh BONE and MUSCLE INTERACTION Ferguson et al. Inhibiting myostatin prevents microgravity-associated bone loss in mice. J Bone Miner Res 24 (Suppl 1). Warner SE, Sanford DA, Becker BA, Bain SD, Srinivasan S, Gross TS. Botox induced muscle paralysis rapidly degrades bone. Bone. 2006 Feb;38(2):257-64. ©2011 Peter R. Cavanagh Short Arm Centrifuges NASA/Wyle Centrifuge ESA/QinetiQ Centrifug (ergometers, vibration plates, and “jojo” inertia wheels) MIT Rotator ©2011 Peter R. Cavanagh Space Cycle Yang, Caiozzo et al. 2007 ©2011 Peter R. Cavanagh Space Cycle with Shark Cage Simulink Model ©2011 Peter R. Cavanagh Without appropriate countermeasures, spaceflight of 2 years or longer will present serious risks due to progressive bone fragility Recapturing Space The National Academies 2011 ©2011 Peter R. Cavanagh BONE : 3 Studies - Methodology Single Photon Absorptiometry Dual Photon Absorptiometry Quantitative Computed Tomography Rambaut and Johnston (1979) (LeBlanc et al. 2000) (Lang et al. 2004) ©2011 Peter R. Cavanagh BONE: BMD changes in Skylab 4 % BMD Loss perBMD Month % Rambaut and Johnston (1979) Single Photon Absorptiometry ©2011 Peter R. Cavanagh BONE: BMD changes in Mir flights % BMD Loss perBMD Month % LeBlanc et al. 1996 Dual Photon Absorptiometry (DXA) ©2011 Peter R. Cavanagh BONE: BMD changes in ISS Missions 0 -0.5 -1 Trabecular Femoral Neck Femoral Spine posterior Spine Spine Trabecular Spine -1.5 Cortical Trochanter Femoral Neck Cortical Femoral Trochanter Trabecular Trochanter -2 % BMD Loss perBMD Month % -2.5 -3 Lang et al. 2004 Quantitative Computed Tomography ©2011 Peter R. Cavanagh BONE: Changes in Strength Strength in stance loading decreased at mean rates of 2.6% (0.6% to 5.0%) per month Strength in fall loading decreased at 2.0% (0.6% to 3.9%) per month Stance strength decrease ~ 2x BMD decrease Keyak et al. 2004 FEM and Quantitative Computed Tomography ©2011 Peter R. Cavanagh BONE: Summary Post Menopausal Male Astronaut Woman on earth on Space Station BMD/Month -0.15% -0.8% -1.4% ©2011 Peter R. Cavanagh BONE : No Progress in a Decade Mir ISS Post menopausal -1.2% women -1.4% per mo per mo 0.15% per mo n=16 LeBlanc et al. 1996 n=18 Lang et al. 2004 ©2011 Peter R. Cavanagh BONE : Recovery after Spaceflight Sibonga et al. 2007 Mir: 28 male, 1 female ISS: 15 male, 2 female ©2011 Peter R. Cavanagh BONE : 50% Recovery Time 300 200 DAYS 100 0 ©2011 Peter R. Cavanagh BONE: Structural Change at 1 Year • Bone mass > 8.1% (from -11%) • vBMD in femoral neck >0.9% • Bone volume >7.2% Lang et al. 2006 Bending strength proportional to moment of inertia: Iyy = p(D4 – d4)/64 Iyy unchanged d -50% D +15% Similar to age-related changes observed by Riggs et al. 2004 ©2011 Peter R. Cavanagh Bone: Mechanisms ©2011 Peter R. Cavanagh Bone Remodeling Courtesy of MSD ©2011 Peter R. Cavanagh Bone: Re-analysis of Skylab Samples Smith et al. (1998) Marker of resorption 32 ©2011 Peter R. Cavanagh Bone: Rodents mechanisms may differ An inhibition of periosteal bone formation occurred during spaceflight in the tibial and humeral diaphyses (of rats). Wronski and Morey 1983 33 ©2011 Peter R. Cavanagh BONE: The Mechanostat: Frost 1987 Strain-based model 100-300ms 1500-3000ms Bone Gain Bone Loss LOADING REPETITIONS ©2011 Peter R. Cavanagh BONE: Loading Houston ISS 8.5 Hrs 9.6 Hrs ©2011 Peter R. Cavanagh BONE : Exercise Countermeasures Peak loading during cycling, walking and running 2.5 2.0 1.5 1.0 Peak Force (Body Weight) (Body Force Peak 0.5 1g 0g 0.0 Cycling Walking Running ©2011 Peter PeakR. Cavanagh loads during running in Zero g were approximately 60% of 1g values Countermeasures: External Loading ©2011 Peter R. Cavanagh Countermeasures: External Loading ©2011 Peter R. Cavanagh Countermeasures: Duration of Loading "Each Station crew member is scheduled for an hour of cardio and an hour of resistive exercise each day while we are on orbit" http://www.nasa.gov/audience/fo reducators/teachingfromspace/da yinthelife/exercise-adil-index.html ©2011 Peter R. Cavanagh Countermeasures: Duration of Loading Short Term Plan: STP 135-150 min. of “scheduled” exercise time ©2011 Peter R. Cavanagh Load Monitoring: Exercise Duration ©2011 Peter R. Cavanagh Activity Monitoring: Actual Loading Duration ©2011 Peter R. Cavanagh Activity Monitoring: Actual Loading Duration Assigned Exercise Time = 146.8 ± 6.28 min Total Loaded Time = 43.11 ± 15.0 min Mean Exercise Efficiency = 29.4% ©2011 Peter R. Cavanagh Exercise Countermeasures: The Bolus Assumption Earth 1BW ISS 1BW ©2011 Peter R. Cavanagh Accumulating Daily Load Required Dose of Loading (Daily Loading Stimulus DLS) for Optimal Bone Health EVA IVA Exercise CM ©2011 Peter R. Cavanagh BONE : The use of osteoprotective drugs Bisphosphonates • LeBlanc et al. 2002 Bedrest. Alendronate attenuated bone loss in 8 male subjects during 17 weeks of horizontal bedrest. • LeBlanc et al. ISS on-orbit experiment in progress • Risk of Bisphosphonates in young individuals ©2011 Peter R. Cavanagh BONE : The use of osteoprotective drugs New Drugs Denosumab FDA approved June 2010, under the trade name Prolia. Human monoclonal antibody inhibits RANK-L Sclerostin gene deletion increased bone formation and bone strength in mice and prevented loss during tail suspension. Li et al 2008, Lin et al. 2009 ©2011 Peter R. Cavanagh The Future Decadal Survey http://www.nap.edu/catalog/13048.html April 2011 ©2011 Peter R. Cavanagh Key Recommendations CHANGE OF FOCUS For the past decade, the emphasis of biological research has been on human countermeasures. The panel is unanimous in its recommendation that an animal habitat should be incorporated as soon as possible into the ISS ©2011 Peter R. Cavanagh Key Recommendations USE OF THE NATIONAL LABORATORY Implementation of decadal research objectivities will have sufficient governmental priority between 2010-2020 to supersede existing NASA operational plans. ©2011 Peter R. Cavanagh Key Recommendations BETTER ACCESS TO ASTRONAUT HEALTH DATA • Implement the Safe Passage report recommendations • Much remains to be done in regard to providing more widespread access to data on astronaut health ©2011 Peter R. Cavanagh Acknowledgements COLLEAGUES COLLABORATORS Jess Snedeker MS PSU 2000 Tom Lang UCSF Jean L.
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