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Project Title:  Approaching Gravity As a Continuum: Musculoskeletal Effects of Fractional Reloading Reduce
Images: icon  Fiscal Year: FY 2024 
Division: Space Biology 
Research Discipline/Element:
Space Biology: Animal Biology: Vertebrate  
Start Date: 10/01/2019  
End Date: 09/30/2022  
Task Last Updated: 07/23/2023 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rutkove, Seward  M.D. / Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Address:  330 Brookline Ave TCC-810  
 
Boston , MA 02215-5400 
Email: srutkove@bidmc.harvard.edu 
Phone: 617-667-8130  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Bouxsein, Mary  Ph.D. Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Key Personnel Changes / Previous PI: None
Project Information: Grant/Contract No. 80NSSC19K1598 
Responsible Center: NASA ARC 
Grant Monitor: Griko, Yuri  
Center Contact: 650-604-0519 
Yuri.V.Griko@nasa.gov 
Unique ID: 12502 
Solicitation / Funding Source: 2018 Space Biology (ROSBio) NNH18ZTT001N-FG. App B: Flight and Ground Space Biology Research 
Grant/Contract No.: 80NSSC19K1598 
Project Type: GROUND 
Flight Program:  
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:
Space Biology Element: (1) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: The effect of full mechanical unloading has been extensively studied in both rodents and humans using ground-based models. Recently, rodent partial weight bearing (PWB) models have revealed that partial gravity provides dose-dependent rescue of the musculoskeletal system as compared to full unloading. Separate work has also shown that after unloading, an abrupt mechanical reloading to 1g causes additional musculoskeletal injury. Here, we propose to employ both PWB and hindlimb unloading models sequentially to investigate gravity as a continuum and its impact on musculoskeletal adaptation to reloading. This work will have critical practical and scientific outcomes, and will provide for the first time, insights into the musculoskeletal responses to adult to fractional gravity after a period of microgravity (as would occur when traveling to Mars). It will also provide information on the mitigating effects of partial gravity after extended unloading. Our Specific Aims are: 1) To determine the physiological adaptations of the musculoskeletal system in males to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, 2) To determine the physiological adaptations of the musculoskeletal system in females to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, and 3) To investigate the potential musculoskeletal benefits of artificial gravity in-flight before returning to Earth. Specifically, we plan to investigate the resulting musculoskeletal alterations in transitioning from 2 weeks of 0g to 0.2, 0.4, and 0.7g, hypothesizing that there is a dose-dependence to the reloading, including recovery and associated injury. We will also assess the potential benefit of using these three levels of PWB as intermediate steps on the way to transitioning back to 1g. Thorough post mortem analyses, we will be able to identify the different processes that might be involved in reloading injury and its mitigation. Stress levels and metabolic/hormonal alterations will also be evaluated. Ultimately, we hope to provide the space biology community a deeper understanding of the musculoskeletal impact of fractional gravity in relation to both microgravity and Earth gravity.

Research Impact/Earth Benefits: Our research will have important implications for the improved understanding of the effects of prolonged disuse on bone and muscle due to bedrest or injury and the effects of rehabilitation. Specifically, lessons learned from this work may help us better understand the negative impact of the re-establishing normal activity after the development of disuse atrophy and the potential for applying graded rehabilitation approaches so as to ensure effective recovery.

Task Progress & Bibliography Information FY2024 
Task Progress: We completed all proposed experiments in males and female rats, aiming at understanding the acute and mid-term adaptation to mechanical reloading following disuse (mimicking microgravity). Moreover, we assessed if partial gravity could be a useful countermeasure when implemented during a mission (by simulating different artificial gravity protocol on the Gateway station, for example). All in vivo and ex vivo analyses have been completed – including muscle function, force production, physiological measurements, muscle histomorphometry, and gene expression using reverse transcription-quantitative polymerase chain reaction (RTqPCR). Organs have been collected and stored for further analysis and for future shipping to the NASA Ames Life Science Data Archive (ALSDA) storage facility. Bone analysis has been performed using peripheral quantitative computed tomography (pQCT) and micro computed tomography (microCT), and serum levels of several bone biomarkers have been performed. Overall, our work demonstrates that males and females react differently to mechanical reloading following disuse, and that bone deconditioning seems to be dramatically impacted by biological sex both during disuse and recovery. For example, we exposed male and female animals to 14 days of hindlimb unloading to induce musculoskeletal deconditioning, before reloading them at 1g for 7d. During the disuse period, females showed a 7% decline in bone mineral density, which was not significantly different than their baseline values. On the other hand, males bone density declined by 20% during the same period, highlighting the greater susceptibility to disuse-induced bone loss in males. While we assumed that 7d of mechanical reloading would lead to bone growth, we did not observe it. Indeed, in males, bone loss continued during the recovery period, at almost an identical rate (approx. -10%/wk).

Bibliography: Description: (Last Updated: 03/05/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Issertine M, Rosa-Caldwell ME, Sung DM, Bouxsein ML, Rutkove SB, Mortreux M. "Adaptation to full weight-bearing following disuse: The impact of biological sex on musculoskeletal health. " 2023 NASA Human Research Program Investigators’ Workshop, “To the Moon: The Next Golden Age of Human Spaceflight”, Galveston, TX, February 7-9, 2023.

Abstracts. 2023 NASA Human Research Program Investigators’ Workshop, “To the Moon: The Next Golden Age of Human Spaceflight”, Galveston, TX, February 7-9, 2023. , Feb-2023

Abstracts for Journals and Proceedings Mortreux M, Rosa-Caldwell ME, Sung DM, Issertine M, Rutkove SB. "Assessing the benefits of artificial gravity on the Gateway: An analog study in males." 2023 NASA Human Research Program Investigators’ Workshop, “To the Moon: The Next Golden Age of Human Spaceflight”, Galveston, TX, February 7-9, 2023.

Abstracts. 2023 NASA Human Research Program Investigators’ Workshop, “To the Moon: The Next Golden Age of Human Spaceflight”, Galveston, TX, February 7-9, 2023. , Feb-2023

Abstracts for Journals and Proceedings Issertine M, Rosa-Caldwell ME, Sung DM, Bouxsein ML, Rutkove SB, Mortreux M. "Adaptation to full weight-bearing following disuse: The impact of biological sex on musculoskeletal health." 38th Annual Meeting of the American Society for Gravitational and Space Research, Houston, TX, November 9-12, 2022.

Abstracts. 38th Annual Meeting of the American Society for Gravitational and Space Research, Houston, TX, November 9-12, 2022. , Nov-2022

Articles in Peer-reviewed Journals Rosa-Caldwell ME, Mortreux M, Wadhwa A, Kaiser UB, Sung DM, Bouxsein ML, Rutkove SB. "Influence of gonadectomy on muscle health in micro- and partial-gravity environments in rats." J Appl Physiol (1985). 2023 May 23. https://doi.org/10.1152/japplphysiol.00023.2023 ; PMID: 37102698; PMCID: PMC10228673 , May-2023
Articles in Peer-reviewed Journals Swain P, Mortreux M, Laws JM, Kyriacou H, De Martino E, Winnard A, Caplan N. "Skeletal muscle deconditioning during partial weight-bearing in rodents – A systematic review and meta-analysis." Life Sci Space Res. 2022 Aug;34:68-86. Review. https://doi.org/10.1016/j.lssr.2022.06.007 , Aug-2022
Articles in Peer-reviewed Journals Swain P, Mortreux M, Laws JM, Kyriacou H, De Martino E, Winnard A, Caplan N. "Bone deconditioning during partial weight-bearing in rodents – A systematic review and meta-analysis." Life Sci Space Res. 2022 Aug;34:87-103. Review. https://doi.org/10.1016/j.lssr.2022.07.003 ; PMID: 35940692 , Aug-2022
Articles in Peer-reviewed Journals Rosa-Caldwell ME, Mortreux M, Wadhwa A, Kaiser UB, Sung D-M, Bouxsein ML, Rutkove SB. "Sex differences in muscle health in simulated micro- and partial-gravity environments in rats." Sports Med Health Sci. 2023 Sep 12. Onine ahead of print. https://doi.org/10.1016/j.smhs.2023.09.002 , Sep-2023
Articles in Peer-reviewed Journals Issertine M, Rosa-Calwell ME, Sung DM, Bouxsein ML, Rutkove SB, Mortreux M. "Adaptation to full weight-bearing following disuse in rats: The impact of biological sex on musculoskeletal recovery." Physiol Rep. 2024 Feb 21;12(4):e15938. https://doi.org/10.14814/phy2.15938 ; PMID: 38383049; PMCID: PMC10881285 , Feb-2024
Project Title:  Approaching Gravity As a Continuum: Musculoskeletal Effects of Fractional Reloading Reduce
Images: icon  Fiscal Year: FY 2023 
Division: Space Biology 
Research Discipline/Element:
Space Biology: Animal Biology: Vertebrate  
Start Date: 10/01/2019  
End Date: 09/30/2022  
Task Last Updated: 07/31/2022 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rutkove, Seward  M.D. / Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Address:  330 Brookline Ave TCC-810  
 
Boston , MA 02215-5400 
Email: srutkove@bidmc.harvard.edu 
Phone: 617-667-8130  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Bouxsein, Mary  Ph.D. Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Key Personnel Changes / Previous PI: None
Project Information: Grant/Contract No. 80NSSC19K1598 
Responsible Center: NASA ARC 
Grant Monitor: Griko, Yuri  
Center Contact: 650-604-0519 
Yuri.V.Griko@nasa.gov 
Unique ID: 12502 
Solicitation / Funding Source: 2018 Space Biology (ROSBio) NNH18ZTT001N-FG. App B: Flight and Ground Space Biology Research 
Grant/Contract No.: 80NSSC19K1598 
Project Type: GROUND 
Flight Program:  
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:
Space Biology Element: (1) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: The effect of full mechanical unloading has been extensively studied in both rodents and humans using ground-based models. Recently, rodent partial weight bearing (PWB) models have revealed that partial gravity provides dose-dependent rescue of the musculoskeletal system as compared to full unloading. Separate work has also shown that after unloading, an abrupt mechanical reloading to 1g causes additional musculoskeletal injury. Here, we propose to employ both PWB and hindlimb unloading models sequentially to investigate gravity as a continuum and its impact on musculoskeletal adaptation to reloading. This work will have critical practical and scientific outcomes, and will provide for the first time, insights into the musculoskeletal responses to adult to fractional gravity after a period of microgravity (as would occur when traveling to Mars). It will also provide information on the mitigating effects of partial gravity after extended unloading. Our Specific Aims are: 1) To determine the physiological adaptations of the musculoskeletal system in males to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, 2) To determine the physiological adaptations of the musculoskeletal system in females to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, and 3) To investigate the potential musculoskeletal benefits of artificial gravity in-flight before returning to Earth. Specifically, we plan to investigate the resulting musculoskeletal alterations in transitioning from 2 weeks of 0g to 0.2, 0.4, and 0.7g, hypothesizing that there is a dose-dependence to the reloading, including recovery and associated injury. We will also assess the potential benefit of using these three levels of PWB as intermediate steps on the way to transitioning back to 1g. Thorough post mortem analyses, we will be able to identify the different processes that might be involved in reloading injury and its mitigation. Stress levels and metabolic/hormonal alterations will also be evaluated. Ultimately, we hope to provide the space biology community a deeper understanding of the musculoskeletal impact of fractional gravity in relation to both microgravity and Earth gravity.

Research Impact/Earth Benefits: Our research will have important implications for the improved understanding of the effects of prolonged disuse on bone and muscle due to bedrest or injury and the effects of rehabilitation. Specifically, lessons learned from this work may help us better understand the negative impact of the re-establishing normal activity after the development of disuse atrophy and the potential for applying graded rehabilitation approaches so as to ensure effective recovery.

Task Progress & Bibliography Information FY2023 
Task Progress: During the last year, all animal experiments have been finalized. Critically, we finished all experiments in males and females, aiming at understanding the acute and mid-term adaptation to mechanical reloading following disuse. Moreover, we assessed if partial gravity could be a useful countermeasure when implemented during a mission (by simulating different artificial gravity protocol on the Gateway station, for example).

All in vivo and ex vivo analyses have been performed (including muscle function, force production, physiological measurements, muscle histomorphometry, gene expression using RTqPCR). Organs have been collected and stored for further analysis and for future shipping to the NASA Ames Life Sciences Data Archive (ALSDA) storage facility. Bone analysis has been performed using peripheral quantitative computed tomography (pQCT) and micro computed tomography (microCT), and serum levels of several bone biomarkers have been performed.

Overall, our work demonstrates that males and females react differently to mechanical reloading following disuse, and that bone deconditioning seems to be dramatically impacted by biological sex, both during disuse and recovery. These data will bring valuable insights to better understand how males and females respond to gravity shifts and allow for the development of targeted countermeasures.

While we have shown that exposure to partial weight-bearing (PWB) leads to a dose-dependent musculoskeletal deconditioning, our results suggest that this could be a useful avenue to explore for long missions (in males).

Over the course of the year, the team has attended 5 conferences, been invited to give 2 seminars, and presented 3 podium talks and 4 posters. Another poster has been accepted for the European Low Gravity Research Association (ELGRA) meeting in Lisbon, Portugal that will take place in September 2022.

Bibliography: Description: (Last Updated: 03/05/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Rosa-Caldwell ME, Mortreux M, Sung DM, Schreurs S, Bouxsein ML, Kaiser U, Rutkove SB. "Sex differences in the etiology of micro-gravity induced musculoskeletal losses are not solely dependent on sex hormones." 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022. , Feb-2022

Abstracts for Journals and Proceedings Mortreux M, Rosa-Caldwell ME, Sung DM, Stiehl ID, Nagy JA, Rutkove SB. "Early muscular response to partial gravity following a bout of disuse in male and female rats." 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022. , Feb-2022

Project Title:  Approaching Gravity As a Continuum: Musculoskeletal Effects of Fractional Reloading Reduce
Images: icon  Fiscal Year: FY 2022 
Division: Space Biology 
Research Discipline/Element:
Space Biology: Animal Biology: Vertebrate  
Start Date: 10/01/2019  
End Date: 09/30/2022  
Task Last Updated: 07/28/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rutkove, Seward  M.D. / Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Address:  330 Brookline Ave TCC-810  
 
Boston , MA 02215-5400 
Email: srutkove@bidmc.harvard.edu 
Phone: 617-667-8130  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Bouxsein, Mary  Ph.D. Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Key Personnel Changes / Previous PI: None
Project Information: Grant/Contract No. 80NSSC19K1598 
Responsible Center: NASA ARC 
Grant Monitor: Griko, Yuri  
Center Contact: 650-604-0519 
Yuri.V.Griko@nasa.gov 
Unique ID: 12502 
Solicitation / Funding Source: 2018 Space Biology (ROSBio) NNH18ZTT001N-FG. App B: Flight and Ground Space Biology Research 
Grant/Contract No.: 80NSSC19K1598 
Project Type: GROUND 
Flight Program:  
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:
Space Biology Element: (1) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: The effect of full mechanical unloading has been extensively studied in both rodents and humans using ground-based models. Recently, rodent partial weight bearing (PWB) models have revealed that partial gravity provides dose-dependent rescue of the musculoskeletal system as compared to full unloading. Separate work has also shown that after unloading, an abrupt mechanical reloading to 1g causes additional musculoskeletal injury. Here, we propose to employ both PWB and hindlimb unloading models sequentially to investigate gravity as a continuum and its impact on musculoskeletal adaptation to reloading. This work will have critical practical and scientific outcomes, and will provide for the first time, insights into the musculoskeletal responses to adult to fractional gravity after a period of microgravity (as would occur when traveling to Mars). It will also provide information on the mitigating effects of partial gravity after extended unloading. Our Specific Aims are: 1) To determine the physiological adaptations of the musculoskeletal system in males to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, 2) To determine the physiological adaptations of the musculoskeletal system in females to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, and 3) To investigate the potential musculoskeletal benefits of artificial gravity in-flight before returning to Earth. Specifically, we plan to investigate the resulting musculoskeletal alterations in transitioning from 2 weeks of 0g to 0.2, 0.4, and 0.7g, hypothesizing that there is a dose-dependence to the reloading, including recovery and associated injury. We will also assess the potential benefit of using these three levels of PWB as intermediate steps on the way to transitioning back to 1g. Thorough post mortem analyses, we will be able to identify the different processes that might be involved in reloading injury and its mitigation. Stress levels and metabolic/hormonal alterations will also be evaluated. Ultimately, we hope to provide the space biology community a deeper understanding of the musculoskeletal impact of fractional gravity in relation to both microgravity and Earth gravity.

Research Impact/Earth Benefits: Our research will have important implications for the improved understanding of the effects of prolonged disuse on bone and muscle due to bedrest or injury and the effects of rehabilitation. Specifically, lessons learned from this work may help us better understand the negative impact of the re-establishing normal activity after the development of disuse atrophy and the potential for applying graded rehabilitation approaches so as to ensure effective recovery.

Task Progress & Bibliography Information FY2022 
Task Progress: Following the COVID-19 pandemic and laboratory shutdown, in vivo experiments have been delayed in 2020. During the first semester (July 2020-December 2020), we worked towards completion of the Aim 1, by assessing how males adjust to partial reloading at 20, 40, and 100% of weight-bearing following an extensive time spent in a microgravity analogue, and thus disused.

As our goal was to assess the existence of a “reloading injury” following disuse, as would be the case when astronauts would land on the Moon, Mars, or Earth following a trip in space, animals were re-ambulated for either 4 or 24 hours and monitored. We did not encounter methodological problems during this experiment and successfully completed all groups by the end of 2020.

Separately, we assessed the impact of disuse on female rats compared to normally-loaded controls, and analyzed all results both in vivo and ex vivo. Therefore, we were able to compare if males and females respond similarly to disuse-induced muscular deconditioning, and submitted a manuscript reflecting our findings in 2021. The manuscript is currently under revision.

In the second semester (January 2021-June 2021), we focused on “reloading injury” following disuse in female animals (Aim 2). We used a paradigm strictly identical to what has been done previously with male rats, and successfully completed the 4 and 24 hours groups for females.

Ex vivo analyses have been completed and a manuscript recapitulating the neuromuscular changes in both sexes is currently in preparation, and should be submitted for publication shortly.

Moreover, we explored the potential relationship between estrous cycle maintenance and musculoskeletal functions using both animals from our current project and previous results. The findings have been summarized in a manuscript that has been submitted for publication in 2021.

Overall, our work this year has aimed to highlight how sex influences animals adaptation to musculoskeletal disuse, and if partial reloading significantly impacts musculoskeletal health.

Bibliography: Description: (Last Updated: 03/05/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Rosa-Caldwell ME, Mortreux M, Sung DM, Schreurs AS, Bouxsein ML, Rutkove SB. "Low testosterone status differentially affects musculoskeletal outcomes after exposure to micro- or partial gravity." 36th Annual Meeting of the American Society for Gravitational and Space Research, Virtual Meeting, November 5-6, 2020.

Abstracts. 36th Annual Meeting of the American Society for Gravitational and Space Research, Virtual Meeting, November 5-6, 2020. , Nov-2020

Abstracts for Journals and Proceedings Mortreux M, Rosa-Caldwell ME, Sung DM, Stiehl ID, Rutkove SB. "Early adaptation to increased mechanical loading after disuse: muscular response in male and female rats." 36th Annual Meeting of the American Society for Gravitational and Space Research, Virtual Meeting, November 5-6, 2020.

Abstracts. 36th Annual Meeting of the American Society for Gravitational and Space Research, Virtual Meeting, November 5-6, 2020. , Nov-2020

Articles in Peer-reviewed Journals Rosa-Caldwell ME, Mortreux M, Kaiser UB, Sung DM, Bouxsein ML, Dunlap KR, Greene NP, Rutkove SB. "The oestrous cycle and skeletal muscle atrophy: Investigations in rodent models of muscle loss." Exp Physiol. 2021 Sep 26. https://doi.org/10.1113/EP089962 ; PMID: 34569104; PMCID: PMC8639792 , Sep-2021
Articles in Peer-reviewed Journals Mortreux M, Rosa-Caldwell ME, Stiehl ID, Sung DM, Thomas NT, Fry CS, Rutkove SB. "Hindlimb suspension in Wistar rats: Sex-based differences in muscle response." Physiol Rep. 2021 Oct;9(19):e15042. https://doi.org/10.14814/phy2.15042 ; PMID: 34612585; PMCID: PMC8493566 , Oct-2021
Articles in Peer-reviewed Journals Mortreux M, Rosa-Caldwell ME. "Approaching gravity as a continuum using the rat partial weight-bearing model. " Life. 2020 Oct 8;10(10):235. Review. https://doi.org/10.3390/life10100235 ; PMID: 33049988; PMCID: PMC7599661 , Oct-2020
Articles in Peer-reviewed Journals Malkani S, Chin CR, Cekanaviciute E, Mortreux M, Okinula H, Tarbier M, Schreurs AS, Shirazi-Fard Y, Tahimic CGT, Rodriguez DN, Sexton BS, Butler D, Verma A, Bezdan D, Durmaz C, MacKay M, Melnick A, Meydan C, Li S, Garrett-Bakelman F, Fromm B, Afshinnekoo E, Langhorst BW, Dimalanta ET, Cheng-Campbell M, Blaber E, Schisler JC, Vanderburg C, Friedländer MR, McDonald JT, Costes SV, Rutkove S, Grabham P, Mason CE, Beheshti A. "Circulating miRNA spaceflight signature reveals targets for countermeasure development." Cell Rep. 2020 Dec 8;33(10):108448. https://doi.org/10.1016/j.celrep.2020.108448 ; PMID: 33242410 , Dec-2020
Articles in Peer-reviewed Journals Willey JS, Britten RA, Blaber E, Tahimic CGT, Chancellor J, Mortreux M, Sanford LD, Kubik AJ, Delp MD, Mao XW. "The individual and combined effects of spaceflight radiation and microgravity on biologic systems and functional outcomes." J Environ Sci Health C Toxicol Carcinog. 2021 Apr 27;39(2):129-79. https://doi.org/10.1080/26896583.2021.1885283 ; PMID: 33902391; PMCID: PMC8274610 , Apr-2021
Project Title:  Approaching Gravity As a Continuum: Musculoskeletal Effects of Fractional Reloading Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Space Biology 
Research Discipline/Element:
Space Biology: Animal Biology: Vertebrate  
Start Date: 10/01/2019  
End Date: 09/30/2022  
Task Last Updated: 07/29/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rutkove, Seward  M.D. / Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Address:  330 Brookline Ave TCC-810  
 
Boston , MA 02215-5400 
Email: srutkove@bidmc.harvard.edu 
Phone: 617-667-8130  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Bouxsein, Mary  Ph.D. Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Project Information: Grant/Contract No. 80NSSC19K1598 
Responsible Center: NASA ARC 
Grant Monitor: Griko, Yuri  
Center Contact: 650-604-0519 
Yuri.V.Griko@nasa.gov 
Unique ID: 12502 
Solicitation / Funding Source: 2018 Space Biology (ROSBio) NNH18ZTT001N-FG. App B: Flight and Ground Space Biology Research 
Grant/Contract No.: 80NSSC19K1598 
Project Type: GROUND 
Flight Program:  
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:
Space Biology Element: (1) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: The effect of full mechanical unloading has been extensively studied in both rodents and humans using ground-based models. Recently, rodent partial weight bearing (PWB) models have revealed that partial gravity provides dose-dependent rescue of the musculoskeletal system as compared to full unloading. Separate work has also shown that after unloading, an abrupt mechanical reloading to 1g causes additional musculoskeletal injury. Here, we propose to employ both PWB and hindlimb unloading models sequentially to investigate gravity as a continuum and its impact on musculoskeletal adaptation to reloading. This work will have critical practical and scientific outcomes, and will provide for the first time, insights into the musculoskeletal responses to adult to fractional gravity after a period of microgravity (as would occur when traveling to Mars). It will also provide information on the mitigating effects of partial gravity after extended unloading. Our Specific Aims are: 1) To determine the physiological adaptations of the musculoskeletal system in males to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, 2) To determine the physiological adaptations of the musculoskeletal system in females to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, and 3) To investigate the potential musculoskeletal benefits of artificial gravity in-flight before returning to Earth. Specifically, we plan to investigate the resulting musculoskeletal alterations in transitioning from 2 weeks of 0g to 0.2, 0.4, and 0.7g, hypothesizing that there is a dose-dependence to the reloading, including recovery and associated injury. We will also assess the potential benefit of using these three levels of PWB as intermediate steps on the way to transitioning back to 1g. Thorough post mortem analyses, we will be able to identify the different processes that might be involved in reloading injury and its mitigation. Stress levels and metabolic/hormonal alterations will also be evaluated. Ultimately, we hope to provide the space biology community a deeper understanding of the musculoskeletal impact of fractional gravity in relation to both microgravity and Earth gravity.

Research Impact/Earth Benefits: Our research will have important implications for the improved understanding of the effects of prolonged disuse on bone and muscle due to bedrest or injury and the effects of rehabilitation. Specifically, lessons learned from this work may help us better understand the negative impact of the re-establishing normal activity after the development of disuse atrophy and the potential for applying graded rehabilitation approaches so as to ensure effective recovery.

Task Progress & Bibliography Information FY2021 
Task Progress: During this initial funding period that began 10/1/2019, we have begun work on Aim 1: studying the impact of short-term reloading after exposure to hindlimb unloading (0g analog). For this paradigm, we first exposed male rats to 14 days of hindlimb suspension (HLS). We then placed the animals either at full loading (PWB100), Martian analog loading (PWB40), or Lunar analog loading (PWB20) for 4 or 24 hours. Muscle health and function were assessed weekly using limb girth, intra-muscular electrical impedance myography (EIM), nerve conduction studies, and grip force. In addition, many biological samples were collected including daily (food intake, body weight) and weekly (blood glucose level, plasmas, feces, urine). Muscles have been analyzed using immunohistochemistry to determine cross-sectional area, myofiber type, and to detect muscle injury. In terms of bone outcomes, we are acquiring peripheral quantitative computerized tomography data and tissue for gene expression studies. Thus far, 68 animals have completed the study.

Due to the COVID-19 pandemic, animal studies were suspended from mid-March until mid-June 2020 and the lab focused on analysis and new manuscripts. However, animal research activities have recommenced and we are making steady progress toward the completion of Aim 1.

Although data collection is underway for the 4 hours reloading groups, we are already quantifying the effects of 14 days of HLS using a pelvic harness and to determine the electrical impedance myography (EIM) parameters that are impacted by weightlessness. While preliminary, our data suggest that short-term reloading (4 and 24 hours) is able to impact muscle health as observed through EIM, grip force, muscle weight, and muscle architecture.

Bibliography: Description: (Last Updated: 03/05/2024) 

Show Cumulative Bibliography
 
Articles in Peer-reviewed Journals Semple C, Riveros D, Sung D-M, Nagy JA, Rutkove SB, Mortreux M. "Using electrical impedance myography as a biomarker of muscle deconditioning in rats exposed to micro- and partial-gravity analogs." Front Physiol. 2020 Sep 15;11:557796. https://doi.org/10.3389/fphys.2020.557796 ; PMID: 33041858; PMCID: PMC7522465 , Sep-2020
Project Title:  Approaching Gravity As a Continuum: Musculoskeletal Effects of Fractional Reloading Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Space Biology 
Research Discipline/Element:
Space Biology: Animal Biology: Vertebrate  
Start Date: 10/01/2019  
End Date: 09/30/2022  
Task Last Updated: 09/23/2019 
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Principal Investigator/Affiliation:   Rutkove, Seward  M.D. / Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Address:  330 Brookline Ave TCC-810  
 
Boston , MA 02215-5400 
Email: srutkove@bidmc.harvard.edu 
Phone: 617-667-8130  
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Organization Type: UNIVERSITY 
Organization Name: Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Joint Agency:  
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Co-Investigator(s)
Affiliation: 
Bouxsein, Mary  Ph.D. Beth Israel Deaconess Medical Center, Inc./Harvard Medical School 
Project Information: Grant/Contract No. 80NSSC19K1598 
Responsible Center: NASA ARC 
Grant Monitor: Griko, Yuri  
Center Contact: 650-604-0519 
Yuri.V.Griko@nasa.gov 
Unique ID: 12502 
Solicitation / Funding Source: 2018 Space Biology (ROSBio) NNH18ZTT001N-FG. App B: Flight and Ground Space Biology Research 
Grant/Contract No.: 80NSSC19K1598 
Project Type: GROUND 
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Space Biology Element: (1) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: The effect of full mechanical unloading has been extensively studied in both rodents and humans using ground-based models. Recently, rodent partial weight bearing (PWB) models have revealed that partial gravity provides dose-dependent rescue of the musculoskeletal system as compared to full unloading. Separate work has also shown that after unloading, an abrupt mechanical reloading to 1g causes additional musculoskeletal injury. Here, we propose to employ both PWB and hindlimb unloading models sequentially to investigate gravity as a continuum and its impact on musculoskeletal adaptation to reloading. This work will have critical practical and scientific outcomes, and will provide for the first time, insights into the musculoskeletal responses to adult to fractional gravity after a period of microgravity (as would occur when traveling to Mars). It will also provide information on the mitigating effects of partial gravity after extended unloading. Our Specific Aims are: 1) To determine the physiological adaptations of the musculoskeletal system in males to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, 2) To determine the physiological adaptations of the musculoskeletal system in females to the fractional gravity of either the Moon or Mars after experiencing microgravity in transit, and 3) To investigate the potential musculoskeletal benefits of artificial gravity in-flight before returning to Earth. Specifically, we plan to investigate the resulting musculoskeletal alterations in transitioning from 2 weeks of 0g to 0.2, 0.4, and 0.7g, hypothesizing that there is a dose-dependence to the reloading, including recovery and associated injury. We will also assess the potential benefit of using these three levels of PWB as intermediate steps on the way to transitioning back to 1g. Thorough post mortem analyses, we will be able to identify the different processes that might be involved in reloading injury and its mitigation. Stress levels and metabolic/hormonal alterations will also be evaluated. Ultimately, we hope to provide the space biology community a deeper understanding of the musculoskeletal impact of fractional gravity in relation to both microgravity and Earth gravity.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2020 
Task Progress: New project for FY2020.

Bibliography: Description: (Last Updated: 03/05/2024) 

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 None in FY 2020