{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T12:51:10Z","timestamp":1777207870899,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,22]]},"group-title":"Cell Biology","reference-count":88,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["R15GM155985"],"award-info":[{"award-number":["R15GM155985"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Huntington\u2019s disease is caused by expansion of a CAG repeat in the human HTT gene, producing a mutant huntingtin protein that misfolds and forms intracellular aggregates. Although Huntington\u2019s disease is primarily characterized as a neurodegenerative disorder, mutant huntingtin is ubiquitously expressed, and peripheral tissues such as skeletal muscle exhibit pathological abnormalities. To define the muscle-intrinsic consequences of pathogenic huntingtin expression, we expressed caspase-6 truncated pathogenic human huntingtin in body wall muscle of\n                  <jats:italic>Drosophila melanogaster<\/jats:italic>\n                  larvae and performed quantitative structural and functional analyses. Aggregate analysis revealed that fluorescence intensity increased with aggregate size while aggregate morphology became more irregular. Delaying transgene expression until later stages of larval development dramatically reduced aggregate number, demonstrating a strong temporal dependence of aggregate formation. Myonuclei were enlarged, misshapen, and exhibited significantly reduced fluorescence intensity, consistent with altered chromatin organization. Notably, huntingtin aggregates were observed within the nucleus, indicating that nuclear proteostasis is directly perturbed by pathogenic huntingtin in muscle cells. Despite these intracellular defects, muscle fiber shape and sarcomere organization were preserved, suggesting that contractile apparatus assembly is not overtly disrupted. In contrast, mitochondrial organization was severely affected, with extensive mitochondrial aggregation throughout muscle fibers, consistent with altered organelle homeostasis. Functional analyses demonstrated that pathogenic huntingtin expression significantly impaired neuromuscular performance. Larvae exhibited reduced excitatory junctional potentials and diminished muscle contractile force, indicating compromised synaptic transmission and muscle function. Together, these findings demonstrate that pathogenic human huntingtin expression in skeletal muscle is sufficient to drive widespread protein aggregation, nuclear and mitochondrial abnormalities, and functional deficits despite the absence of overt structural changes. Our results highlight the importance of muscle-intrinsic pathogenic mechanisms and provide a quantitative framework for understanding how mutant huntingtin disrupts cellular organization and physiology outside the nervous system.\n                <\/jats:p>","DOI":"10.64898\/2026.04.20.719674","type":"posted-content","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:50:20Z","timestamp":1776919820000},"source":"Crossref","is-referenced-by-count":0,"title":["Pathogenic human huntingtin expression causes prolific intramuscular aggregation, leading to nuclear, metabolic, and physiological dysregulation in striated muscle"],"prefix":"10.64898","author":[{"given":"Tadros A.","family":"Hana","sequence":"first","affiliation":[{"name":"University of Toledo, Neuroscience and Psychiatry Department, Toledo, OH, U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9739-8777","authenticated-orcid":false,"given":"Kiel G.","family":"Ormerod","sequence":"additional","affiliation":[{"name":"University of Toledo, Neuroscience and Psychiatry Department, Toledo, OH, U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026042605300440000_2026.04.20.719674v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.12.013"},{"key":"2026042605300440000_2026.04.20.719674v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2014.24"},{"key":"2026042605300440000_2026.04.20.719674v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12426"},{"key":"2026042605300440000_2026.04.20.719674v1.4","doi-asserted-by":"crossref","first-page":"e1058464","DOI":"10.1080\/21675511.2015.1058464","article-title":"Huntington\u2019s disease is a multi-system disorder","volume":"3","year":"2015","journal-title":"Rare Diseases"},{"key":"2026042605300440000_2026.04.20.719674v1.5","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3233\/JHD-210488","article-title":"Quantifying the Onset of Unintended Weight Loss in Huntington\u2019s Disease: A Retrospective Analysis of Enroll-HD","volume":"10","year":"2021","journal-title":"J. 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