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HCM is associated with progressive tissue-level disarray and subcellular disorganization in individual cardiomyocytes. Mutations in \u03b2-cardiac myosin (MYH7), the second most common genetic cause of HCM, commonly result in changes in sarcomeric force production, but how this leads to altered cell- and tissue-level organization is unclear. Here, we use cryo-electron tomography (cryo-ET) to bridge the molecular and cellular scales by visualizing the nanoscale organization of individual myosin-containing thick filaments within sarcomeres of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Compared to isogenic wild-type controls, hiPSC-CMs expressing P710R MYH7 exhibit pronounced disruption of the hexagonal packing of thick filaments within individual sarcomeres, which would be difficult to visualize using conventional light microscopy or even room-temperature electron microscopy. We also observe ribosome infiltration into areas of sarcomeric disorder for both wild-type and P710R MYH7 hiPSC-CMs, suggesting that disordered regions may be sites of local proteostasis or remodeling. Together, these data illuminate how altered myosin activity can propagate to yield dramatic changes in sarcomeric organization in HCM.<\/jats:p>","DOI":"10.64898\/2026.02.18.706593","type":"posted-content","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T07:35:17Z","timestamp":1771486517000},"source":"Crossref","is-referenced-by-count":1,"title":["Cryo-ET reveals nanoscale thick filament disorganization in MYH7 P710R hypertrophic cardiomyopathy cardiomyocytes"],"prefix":"10.64898","author":[{"given":"Magda","family":"Zaoralov\u00e1","sequence":"first","affiliation":[{"name":"CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA, USA"},{"name":"Department of Bioengineering, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Yoniles","sequence":"additional","affiliation":[{"name":"Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prerna","family":"Giri","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard G.","family":"Held","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Vander Roest","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Dahlberg","sequence":"additional","affiliation":[{"name":"CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA, USA"},{"name":"Department of Structural Biology, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Bernstein","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander R.","family":"Dunn","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5329-4300","authenticated-orcid":false,"given":"Leeya","family":"Engel","sequence":"additional","affiliation":[{"name":"Faculty of Mechanical Engineering, Technion - 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