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Targeted\/personalized therapeutics are at the forefront of space medicine strategies, and cross-species molecular signatures now define the \u2018typical\u2019 spaceflight response. However, a lack of direct genotype\u2013phenotype associations currently limits the robustness and, therefore, the therapeutic utility of putative mechanisms underpinning pathological changes in flight. Methods: We employed the worm Caenorhabditis elegans as a validated model of space biology, combined with \u2018NemaFlex-S\u2019 microfluidic devices for assessing animal strength production as one of the most reproducible physiological responses to spaceflight. Wild-type and dys-1 (BZ33) strains (a Duchenne muscular dystrophy (DMD) model for comparing predisposed muscle weak animals) were cultured on the International Space Station in chemically defined media before loading second-generation gravid adults into NemaFlex-S devices to assess individual animal strength. These same cultures were then frozen on orbit before returning to Earth for next-generation sequencing transcriptomic analysis. Results: Neuromuscular strength was lower in flight versus ground controls (16.6% decline, p &lt; 0.05), with dys-1 significantly more (23% less strength, p &lt; 0.01) affected than wild types. The transcriptional gene ontology signatures characterizing both strains of weaker animals in flight strongly corroborate previous results across species, enriched for upregulated stress response pathways and downregulated mitochondrial and cytoskeletal processes. Functional gene cluster analysis extended this to implicate decreased neuronal function, including abnormal calcium handling and acetylcholine signaling, in space-induced strength declines under the predicted control of UNC-89 and DAF-19 transcription factors. Finally, gene modules specifically altered in dys-1 animals in flight again cluster to neuronal\/neuromuscular pathways, suggesting strength loss in DMD comprises a strong neuronal component that predisposes these animals to exacerbated strength loss in space. Conclusions: Highly reproducible gene signatures are strongly associated with space-induced neuromuscular strength loss across species and neuronal changes in calcium\/acetylcholine signaling require further study. These results promote targeted medical efforts towards and provide an in vivo model for safely sending animals and people into deep space in the near future.<\/jats:p>","DOI":"10.3390\/cells12202470","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T08:10:19Z","timestamp":1697530219000},"page":"2470","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Spaceflight Induces Strength Decline in Caenorhabditis elegans"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6531-7197","authenticated-orcid":false,"given":"Purushottam","family":"Soni","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunter","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taslim","family":"Anupom","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizanur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Lesanpezeshki","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2446-3654","authenticated-orcid":false,"given":"Jerzy","family":"Blawzdziewicz","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, Texas Tech University, Lubbock, TX 79409, USA"},{"name":"Department of Physics and Astronomy, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4984-0567","authenticated-orcid":false,"given":"Henry","family":"Cope","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Nottingham, Derby DE22 3DT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nima","family":"Gharahdaghi","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Nottingham, Derby DE22 3DT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Scott","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li Shean","family":"Toh","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip M.","family":"Williams","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Etheridge","sequence":"additional","affiliation":[{"name":"Department of Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter, Exeter EX1 2LU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4425-9746","authenticated-orcid":false,"given":"Nathaniel","family":"Szewczyk","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Nottingham, Derby DE22 3DT, UK"},{"name":"Ohio Musculoskeletal and Neurological Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig R. G.","family":"Willis","sequence":"additional","affiliation":[{"name":"School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6036-1949","authenticated-orcid":false,"given":"Siva A.","family":"Vanapalli","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41526-023-00285-0","article-title":"Microbial Applications for Sustainable Space Exploration beyond Low Earth Orbit","volume":"9","author":"Koehle","year":"2023","journal-title":"npj Microgravity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41526-020-00124-6","article-title":"Red Risks for a Journey to the Red Planet: The Highest Priority Human Health Risks for a Mission to Mars","volume":"6","author":"Patel","year":"2020","journal-title":"npj Microgravity"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e12834","DOI":"10.1111\/jpi.12834","article-title":"Physiological Consequences of Space Flight, Including Abnormal Bone Metabolism, Space Radiation Injury, and Circadian Clock Dysregulation: Implications of Melatonin Use and Regulation as a Countermeasure","volume":"74","author":"Hirayama","year":"2023","journal-title":"J. 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