{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T14:50:07Z","timestamp":1780066207970,"version":"3.54.0"},"posted":{"date-parts":[[2026,2,18]]},"group-title":"Physiology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["AG048262"],"award-info":[{"award-number":["AG048262"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["AR08281"],"award-info":[{"award-number":["AR08281"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["AR057347"],"award-info":[{"award-number":["AR057347"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Aging and disuse are two of the most clinically relevant conditions associated with the loss of skeletal muscle mass, yet the ultrastructural adaptations that drive these losses remain poorly defined. In particular, it is unclear whether radial atrophy of muscle fibers is driven by a reduction in the size of the existing myofibrils, and\/or the loss of myofibrils. Accordingly, the objective of this study was to define the macro-to-ultrastructural adaptations that mediate aging- and disuse-induced loss of muscle mass.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Skeletal muscle structure was assessed at the macroscopic, microscopic, and ultrastructural levels in humans and mice. In humans, magnetic resonance imaging was used to quantify knee extensor muscle volume and cross-sectional area (CSA) in young (19 - 40 years) and old (65 - 84 years) adults, and vastus lateralis biopsies were analyzed for microscopic and ultrastructural adaptations using immunohistochemistry and fluorescence imaging of myofibrils with image deconvolution (FIM-ID). Parallel studies were performed in young (4 months) and aged (24 months) mice, along with the use of unilateral hindlimb immobilization to model disuse.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Aging led to a robust loss of skeletal muscle mass that was mediated by coordinated macro-to-ultrastructural adaptations. In humans, aging reduced knee extensor muscle volume (34%,\n                    <jats:italic>P &lt;<\/jats:italic>\n                    0.005) and CSA (32%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.001) in a sex-independent manner, and these effects were associated with radial atrophy of SERCA1-positive fibers (23%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05). Ultrastructural analyses revealed that the radial atrophy was driven by a reduction in the number of myofibrils per fiber (23%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05) without changes in myofibril CSA. In mice, aging produced similar macro-to-ultrastructural adaptations in various flexor muscles; however, radial atrophy of the highly glycolytic\/Type IIb fibers, which are not present in human limb muscles, was also associated with a decrease in the CSA of the myofibrils (9%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.005). We also determined that disuse led to radial atrophy of SERCA1-positive fibers (24%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.001), and this was mediated by a decrease in both the number (22%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.005) and size of the myofibrils (4%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05). Notably, the results also revealed that the magnitude of the disuse-induced adaptations was significantly blunted with aging.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This study identifies the loss of myofibrils as a central and conserved mediator of the radial atrophy of muscle fibers that occurs in response to disuse and aging, while also highlighting smaller context-dependent contributions that can arise from changes in myofibril size.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.16.706166","type":"posted-content","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T16:40:13Z","timestamp":1771432813000},"source":"Crossref","is-referenced-by-count":1,"title":["Macroscopic to Ultrastructural Analyses Identify the Loss of Myofibrils as the Primary Mediator of Muscle Fiber Atrophy in Aging and Disuse"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4467-6742","authenticated-orcid":false,"given":"Ramy K. A.","family":"Sayed","sequence":"first","affiliation":[{"name":"Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony N.","family":"Lange","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7381-6006","authenticated-orcid":false,"given":"Hector G.","family":"Paez","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7327-6460","authenticated-orcid":false,"given":"Jamie E.","family":"Hibbert","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2469-5827","authenticated-orcid":false,"given":"Marius","family":"Meinhold","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey G.K.","family":"Flynn","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilde B.Z.","family":"Vergara","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabell","family":"Dobrzycki","sequence":"additional","affiliation":[{"name":"Exercise and Rehabilitation Sciences Program, Department of Physical Therapy, Marquette University, Milwaukee, WI, USA"},{"name":"Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin\u2013Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Wrucke","sequence":"additional","affiliation":[{"name":"Exercise and Rehabilitation Sciences Program, Department of Physical Therapy, Marquette University, Milwaukee, WI, USA"},{"name":"Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin\u2013Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos S.","family":"Zepeda","sequence":"additional","affiliation":[{"name":"Exercise and Rehabilitation Sciences Program, Department of Physical Therapy, Marquette University, Milwaukee, WI, USA"},{"name":"Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin\u2013Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4712-5834","authenticated-orcid":false,"given":"Jessica J.","family":"James","sequence":"additional","affiliation":[{"name":"Exercise and Rehabilitation Sciences Program, Department of Physical Therapy, Marquette University, Milwaukee, WI, USA"},{"name":"Department of Kinesiology, University of Wisconsin\u2013Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6709-4078","authenticated-orcid":false,"given":"Christopher W.","family":"Sundberg","sequence":"additional","affiliation":[{"name":"Exercise and Rehabilitation Sciences Program, Department of Physical Therapy, Marquette University, Milwaukee, WI, USA"},{"name":"Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin\u2013Madison, Madison, WI, USA"},{"name":"Department of Kinesiology, University of Wisconsin\u2013Madison, Madison, WI, USA"},{"name":"Athletic and Human Performance Research Center, Marquette University, Milwaukee, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2349-1899","authenticated-orcid":false,"given":"Troy A.","family":"Hornberger","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026022011551474000_2026.02.16.706166v1.1","doi-asserted-by":"crossref","unstructured":"Janssen I , Heymsfield SB , Wang Z , Ross R . Skeletal muscle mass and distribution in 468 men and women aged 18\u201388 yr. Journal of applied physiology. 2000;","DOI":"10.1152\/jappl.2000.89.1.81"},{"key":"2026022011551474000_2026.02.16.706166v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s10522-015-9631-7"},{"key":"2026022011551474000_2026.02.16.706166v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05177-6"},{"key":"2026022011551474000_2026.02.16.706166v1.4","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnaa016"},{"key":"2026022011551474000_2026.02.16.706166v1.5","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/84.3.475"},{"key":"2026022011551474000_2026.02.16.706166v1.6","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1002\/jcsm.12928","article-title":"Association between skeletal muscle mass and quality of life in adults with cancer: a systematic review and meta-analysis","volume":"13","year":"2022","journal-title":"Journal of cachexia, sarcopenia and muscle"},{"key":"2026022011551474000_2026.02.16.706166v1.7","doi-asserted-by":"crossref","unstructured":"Li R , Xia J , Zhang X , Gathirua-Mwangi WG , Guo J , Li Y , et al. Associations of muscle mass and strength with all-cause mortality among US older adults. Medicine and science in sports and exercise. 2018;50:458.","DOI":"10.1249\/MSS.0000000000001448"},{"key":"2026022011551474000_2026.02.16.706166v1.8","doi-asserted-by":"publisher","DOI":"10.1136\/jech-2019-212268"},{"key":"2026022011551474000_2026.02.16.706166v1.9","doi-asserted-by":"crossref","unstructured":"Sizoo D , Stam SP , de Heide LJ , Emous M , van Zutphen T , van Dijk PR , et al. The association of low muscle mass with prevalence and incidence of type 2 diabetes in different BMI classes. Diabetes Research and Clinical Practice. 2023;195:110197.","DOI":"10.1016\/j.diabres.2022.110197"},{"key":"2026022011551474000_2026.02.16.706166v1.10","doi-asserted-by":"publisher","DOI":"10.3390\/cells9071658"},{"key":"2026022011551474000_2026.02.16.706166v1.11","doi-asserted-by":"publisher","DOI":"10.3390\/cells12242811"},{"key":"2026022011551474000_2026.02.16.706166v1.12","doi-asserted-by":"crossref","unstructured":"Larsson L , Degens H , Li M , Salviati L , Il Lee Y , Thompson W , et al. Sarcopenia: aging-related loss of muscle mass and function. Physiological reviews. 2018;","DOI":"10.1152\/physrev.00061.2017"},{"key":"2026022011551474000_2026.02.16.706166v1.13","doi-asserted-by":"crossref","unstructured":"Gustafsson T , Ulfhake B . Aging skeletal muscles: what are the mechanisms of age-related loss of strength and muscle mass, and can we impede its development and progression? International journal of molecular sciences. 2024;25:10932.","DOI":"10.3390\/ijms252010932"},{"key":"2026022011551474000_2026.02.16.706166v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(88)90132-3"},{"key":"2026022011551474000_2026.02.16.706166v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2013.02.012"},{"key":"2026022011551474000_2026.02.16.706166v1.16","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00425.2021"},{"key":"2026022011551474000_2026.02.16.706166v1.17","doi-asserted-by":"crossref","first-page":"8884","DOI":"10.3390\/jcm14248884","article-title":"Quantifying the Toll of Disuse: A Meta-Analysis of Skeletal Muscle Mass and Strength Loss Following Upper Limb Immobilization","volume":"14","year":"2025","journal-title":"Journal of Clinical Medicine"},{"key":"2026022011551474000_2026.02.16.706166v1.18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033232"},{"key":"2026022011551474000_2026.02.16.706166v1.19","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1249\/MSS.0000000000002922","article-title":"Early Changes of Hamstrings Morphology and Contractile Properties during 10 d of Complete Inactivity","volume":"54","year":"2022","journal-title":"Medicine and Science in Sports and Exercise"},{"key":"2026022011551474000_2026.02.16.706166v1.20","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00799.2015"},{"key":"2026022011551474000_2026.02.16.706166v1.21","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.15042"},{"key":"2026022011551474000_2026.02.16.706166v1.22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.1977.tb00274.x"},{"key":"2026022011551474000_2026.02.16.706166v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(78)90002-3"},{"key":"2026022011551474000_2026.02.16.706166v1.24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1993.tb09573.x"},{"key":"2026022011551474000_2026.02.16.706166v1.25","doi-asserted-by":"publisher","DOI":"10.1113\/jp276018"},{"key":"2026022011551474000_2026.02.16.706166v1.26","doi-asserted-by":"crossref","unstructured":"Jorgenson KW , Hibbert JE , Sayed RK , Lange AN , Godwin JS , Mesquita PH , et al. A novel imaging method (FIM-ID) reveals that myofibrillogenesis plays a major role in the mechanically induced growth of skeletal muscle. Elife. 2024;12:RP92674.","DOI":"10.7554\/eLife.92674"},{"key":"2026022011551474000_2026.02.16.706166v1.27","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1242\/dmm.019414","article-title":"The role of mTOR signaling in the regulation of protein synthesis and muscle mass during immobilization in mice","volume":"8","year":"2015","journal-title":"Disease Models & Mechanisms"},{"key":"2026022011551474000_2026.02.16.706166v1.28","doi-asserted-by":"publisher","DOI":"10.3390\/cells10092459"},{"key":"2026022011551474000_2026.02.16.706166v1.29","doi-asserted-by":"crossref","unstructured":"Ahmed ME , Bando H , Fuse S , Abdelfattah HM , Ahmed ME , Ahmed MA-K , et al. Differential isoform expression of SERCA and myosin heavy chain in hypopharyngeal muscles. ACTA Otorhinolaryngologica Italica. 2019;39:220.","DOI":"10.14639\/0392-100X-2185"},{"key":"2026022011551474000_2026.02.16.706166v1.30","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.1007\/s11357-024-01082-7","article-title":"Translatability of mouse muscle-aging for humans: the role of sex","volume":"46","year":"2024","journal-title":"Geroscience"},{"key":"2026022011551474000_2026.02.16.706166v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108796"},{"key":"2026022011551474000_2026.02.16.706166v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5320(70)90166-8"},{"key":"2026022011551474000_2026.02.16.706166v1.33","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-004-0717-6"},{"key":"2026022011551474000_2026.02.16.706166v1.34","doi-asserted-by":"crossref","unstructured":"Harrison BC , Allen DL , Leinwand LA . IIb or not IIb? Regulation of myosin heavy chain gene expression in mice and men. Skeletal muscle. 2011;1:5.","DOI":"10.1186\/2044-5040-1-5"},{"key":"2026022011551474000_2026.02.16.706166v1.35","doi-asserted-by":"crossref","first-page":"E627","DOI":"10.1152\/ajpendo.1996.270.4.E627","article-title":"Prolonged bed rest decreases skeletal muscle and whole body protein synthesis","volume":"270","year":"1996","journal-title":"American Journal of Physiology-Endocrinology and Metabolism"},{"key":"2026022011551474000_2026.02.16.706166v1.36","doi-asserted-by":"publisher","DOI":"10.1113\/JP271188"},{"key":"2026022011551474000_2026.02.16.706166v1.37","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00703.2016"},{"key":"2026022011551474000_2026.02.16.706166v1.38","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00422.2018"},{"key":"2026022011551474000_2026.02.16.706166v1.39","doi-asserted-by":"crossref","unstructured":"Yanai S , Endo S . Functional aging in male C57BL\/6J mice across the life-span: a systematic behavioral analysis of motor, emotional, and memory function to define an aging phenotype. Frontiers in aging neuroscience. 2021;13:697621.","DOI":"10.3389\/fnagi.2021.697621"},{"key":"2026022011551474000_2026.02.16.706166v1.40","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00768.2022"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.02.16.706166","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T19:55:34Z","timestamp":1771617334000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.02.16.706166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,18]]},"references-count":40,"URL":"https:\/\/doi.org\/10.64898\/2026.02.16.706166","relation":{},"subject":[],"published":{"date-parts":[[2026,2,18]]},"subtype":"preprint"}}