{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:19:10Z","timestamp":1785403150371,"version":"3.56.0"},"posted":{"date-parts":[[2025,11,3]]},"group-title":"Cell Biology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/00p5z3m34","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R37 CA299888"],"award-info":[{"award-number":["R37 CA299888"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 HL159436"],"award-info":[{"award-number":["R01 HL159436"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RGS-24-1258280"],"award-info":[{"award-number":["RGS-24-1258280"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032645","name":"Hevolution Foundation","doi-asserted-by":"crossref","award":["HF-GRO-23-1199172-46"],"award-info":[{"award-number":["HF-GRO-23-1199172-46"]}],"id":[{"id":"10.13039\/100032645","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by mutations in the\n                    <jats:italic>TAFAZZIN<\/jats:italic>\n                    gene, which disrupts cardiolipin (CL) remodeling and mitochondrial function. While cardiac manifestations of BTHS are well characterized, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We investigated neuromuscular and mitochondrial alterations in a novel murine model (Taz\n                    <jats:sup>PM<\/jats:sup>\n                    ) carrying a patient-derived D75H point mutation in\n                    <jats:italic>Tafazzin<\/jats:italic>\n                    . This mutation preserves protein abundance but abolishes enzymatic activity. Skeletal muscle function was assessed via weightlifting and hanging tests. Muscle fiber composition and neuromuscular junction (NMJ) integrity were evaluated using immunofluorescence, western blotting, and in vivo electrophysiology. Mitochondrial morphology was examined by transmission electron microscopy, and bioenergetics were quantified using ultra-performance liquid chromatography. Stress signaling was assessed by western blotting.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Male Taz\n                    <jats:sup>PM<\/jats:sup>\n                    mice exhibited elevated monolysocardiolipin and reduced mature CL levels, confirming deficient transacylase activity. These mice exhibited lower muscle strength and endurance, smaller muscle fibers of all types, and a shift toward fast-twitch type 2B fibers, which are more susceptible to fatigue. Electrophysiological analysis revealed a 60% reduction in motor unit number and an increase in average single motor unit potential, indicating motor neuron remodeling. NMJ protein analysis showed decreased MUSK and DOK7 and increased CHRNA1, suggesting impaired NMJ integrity. Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins (NDUFB8, MCU, TMEM65), resting ATP, phosphocreatine, and adenine nucleotide ratios were unchanged in both glycolytic and oxidative muscles. However, stress signaling pathways were markedly activated, including phosphorylation of eIF2\u03b1, increased CHOP, DELE1, p53 expression, and altered Wnt\/\u03b2-catenin signaling components.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Deficiency of Tafazzin enzymatic activity in skeletal muscle is sufficient to result in widespread neuromuscular remodeling, including fiber size\/type shifts, motor unit loss, NMJ dysregulation, and stress pathway activation, without overt energetic failure at rest. These findings suggest that myopathy in BTHS arises not solely from mitochondrial ATP insufficiency but rather from cumulative structural and signaling disruptions.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.31.685856","type":"posted-content","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T10:30:23Z","timestamp":1762165823000},"source":"Crossref","is-referenced-by-count":0,"title":["Deficient Cardiolipin Remodeling Alters Muscle Fiber Composition and Neuromuscular Connectivity in Barth Syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8751-6530","authenticated-orcid":false,"given":"Catalina","family":"Matias","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige L.","family":"Snider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Sierra Potchanant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8632-5791","authenticated-orcid":false,"given":"Joshua R.","family":"Huot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8288-7992","authenticated-orcid":false,"given":"Rahul","family":"Raghav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3065-8498","authenticated-orcid":false,"given":"Michael T.","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5593-9259","authenticated-orcid":false,"given":"Simon J.","family":"Conway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3503-0528","authenticated-orcid":false,"given":"Jeffrey J.","family":"Brault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025110423300627000_2025.10.31.685856v1.1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.mito.2015.01.002","article-title":"Tafazzins from Drosophila and mammalian cells assemble in large protein complexes with a short half-life","volume":"21","year":"2015","journal-title":"Mitochondrion"},{"key":"2025110423300627000_2025.10.31.685856v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.04.016"},{"key":"2025110423300627000_2025.10.31.685856v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1064"},{"key":"2025110423300627000_2025.10.31.685856v1.4","doi-asserted-by":"crossref","unstructured":"Claypool SM , Boontheung P , McCaffery JM , Loo JA , Koehler CM . 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