{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T09:03:46Z","timestamp":1790154226704,"version":"4.0.1"},"reference-count":37,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI22\/01587"],"award-info":[{"award-number":["PI22\/01587"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Quantitative muscle MRI is increasingly used to assess structural muscle damage in inherited myopathies, but its application in primary mitochondrial myopathies (PMM) has not been systematically evaluated in large cohorts. Because PMM are clinically and genetically heterogeneous, objective imaging biomarkers are needed to quantify skeletal\u2010muscle involvement and define meaningful subgroups. We assessed whether MRI\u2010derived proton density fat fraction (PDFF) captures genotype\u2010 and phenotype\u2010specific patterns of fatty replacement and reflects disease severity using motor function outcomes and circulating biomarkers.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We performed a cross\u2010sectional analysis of 49 adults with genetically confirmed PMM enrolled in a prospective natural history study. Participants underwent standardised lower\u2010limb MRI, including T1\u2010weighted sequences and mDIXON\u2010QUANT fat fraction imaging. Muscle involvement was assessed semi\u2010quantitatively with the modified Mercuri scale and quantitatively by PDFF measurement in selected pelvic girdle and thigh muscles. A total fat fraction score (FF sum) was calculated. PDFF was compared across genotypes and phenotypes and against MRC score, NSAA, 6\u2010min walk test, 100\u2010m run test, CK, serum creatinine, GDF15 and disease duration.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Mean age at onset was 26.3\u2009\u00b1\u200915.1\u2009years, mean age at MRI was 50.0\u2009\u00b1\u200912.3\u2009years, and median disease duration was 23\u2009years (IQR 15\u201331). Genetic diagnoses included mtDNA variants in 29 patients (59.1%; single large\u2010scale deletions,\n n<\/jats:italic>\n \u2009=\u200919; point mutations,\n n<\/jats:italic>\n \u2009=\u200910), nuclear variants in\n POLG<\/jats:italic>\n (\n n<\/jats:italic>\n \u2009=\u20098),\n TK2<\/jats:italic>\n (\n n<\/jats:italic>\n \u2009=\u20098) and\n TWNK<\/jats:italic>\n (\n n<\/jats:italic>\n \u2009=\u20094). Phenotypes were exercise intolerance without overt weakness (\n n<\/jats:italic>\n \u2009=\u20097), isolated progressive external ophthalmoplegia (PEO;\n n<\/jats:italic>\n \u2009=\u200916), PEO\u2010plus (\n n<\/jats:italic>\n \u2009=\u200916) and progressive myopathy (\n n<\/jats:italic>\n \u2009=\u20098). Highest median PDFF values were observed in\n tensor fasciae latae<\/jats:italic>\n (31%),\n gluteus maximus<\/jats:italic>\n (30%),\n sartorius<\/jats:italic>\n (25%) and\n gracilis<\/jats:italic>\n (20%). FF sum correlated with MRC score (\n r<\/jats:italic>\n \u2009=\u2009\u22120.567,\n p<\/jats:italic>\n \u2009<\u20090.0001), NSAA (\n r<\/jats:italic>\n \u2009=\u2009\u22120.731,\n p<\/jats:italic>\n \u2009<\u20090.0001), 100\u2010m run test time (\n r<\/jats:italic>\n \u2009=\u20090.629,\n p<\/jats:italic>\n \u2009<\u20090.0001), 6\u2010min walk distance (\n r<\/jats:italic>\n \u2009=\u2009\u22120.311,\n p<\/jats:italic>\n \u2009=\u20090.0476) and serum creatinine (\n r<\/jats:italic>\n \u2009=\u2009\u22120.715,\n p<\/jats:italic>\n \u2009<\u20090.0001), but not with CK or GDF15. TK2 deficiency showed the highest fat replacement, particularly in\n gluteus maximus<\/jats:italic>\n and\n gracilis<\/jats:italic>\n (\n p<\/jats:italic>\n \u2009<\u20090.001). Progressive myopathy showed greater fatty replacement than other phenotypes (\n p<\/jats:italic>\n \u2009<\u20090.001), while exercise intolerance showed higher fat fraction than isolated PEO (\n p<\/jats:italic>\n \u2009=\u20090.033).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Quantitative muscle MRI provides objective and clinically meaningful measures of muscle involvement in PMM. MRI\u2010derived fat fraction reflects disease severity, discriminates between genotypes and phenotypes, and detects subclinical muscle damage. These cross\u2010sectional findings support PDFF as a candidate imaging biomarker for patient stratification and disease characterisation; prospective longitudinal studies will be required to establish its sensitivity to change and its validity as an outcome measure for therapeutic trials.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70380","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:47:22Z","timestamp":1789480042000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantitative Muscle MRI Fat Fraction as a Biomarker of Disease Severity in Mitochondrial Myopathies"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5809-9101","authenticated-orcid":false,"given":"Ana","family":"Bermejo\u2010Mori\u00f1igo","sequence":"first","affiliation":[{"name":"Radiology Department Hospital Universitario 12 de Octubre Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6892-3632","authenticated-orcid":false,"given":"Paloma","family":"Mart\u00edn\u2010Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Unit, Neurology Department Hospital Universitario 12 de Octubre Madrid Spain"},{"name":"Medical\u2010Surgical Sciences Research, Faculty of Medicine Complutense University of Madrid Madrid Spain"},{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019 Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (imas12) Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5102-3718","authenticated-orcid":false,"given":"Violeta","family":"Gonz\u00e1lez\u2010M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Radiology Department Hospital Universitario 12 de Octubre Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8349-715X","authenticated-orcid":false,"given":"Laura","family":"Bermejo\u2010Guerrero","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Unit, Neurology Department Hospital Universitario 12 de Octubre Madrid Spain"},{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019 Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (imas12) Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1930-574X","authenticated-orcid":false,"given":"Luz Edith","family":"Ochoa","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019 Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (imas12) Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2147-2811","authenticated-orcid":false,"given":"Cristina","family":"Mart\u00edn\u2010Arriscado","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n y Soporte Cient\u00edfico Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (imas12) Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6705-0059","authenticated-orcid":false,"given":"Andrea","family":"Alcal\u00e1\u2010Galiano","sequence":"additional","affiliation":[{"name":"Radiology Department Hospital Universitario 12 de Octubre Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Casado\u2010P\u00e9rez","sequence":"additional","affiliation":[{"name":"Radiology Department Hospital Universitario 12 de Octubre Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9013-6427","authenticated-orcid":false,"given":"Mar\u00eda","family":"Navarro\u2010Riquelme","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019 Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (imas12) Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2856-4399","authenticated-orcid":false,"given":"Roc\u00edo","family":"Garrido\u2010Moraga","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019 Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (imas12) Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4011-362X","authenticated-orcid":false,"given":"Adri\u00e1n","family":"Gonz\u00e1lez Quintana","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019 Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (imas12) Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6479-3615","authenticated-orcid":false,"given":"Alberto","family":"Bl\u00e1zquez","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019 Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (imas12) Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5151-988X","authenticated-orcid":false,"given":"Cristina","family":"Dom\u00ednguez\u2010Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Unit, Neurology Department Hospital Universitario 12 de Octubre Madrid Spain"},{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019 Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (imas12) Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III Madrid 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