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Here, we explore how different muscles of one individual\u2014extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles\u2014respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a mouse model for mitochondrial myopathy (\u201cdeletor\u201d), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single\u2010nuclear RNA\u2010sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito\u2010QC marker mice crossed to deletors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one\u2010carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl\u2010CoA synthesis and fatty\u2010acid oxidation pathways, and accumulate lipids. In QFs, <jats:italic>Pdk4<\/jats:italic> transcription is not induced.\u2010 Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non\u2010optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non\u2010optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70404","type":"journal-article","created":{"date-parts":[[2025,7,19]],"date-time":"2025-07-19T02:28:46Z","timestamp":1752892126000},"source":"Crossref","is-referenced-by-count":4,"title":["PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3173-6542","authenticated-orcid":false,"given":"Swagat","family":"Pradhan","sequence":"first","affiliation":[{"name":"Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Mito","sequence":"additional","affiliation":[{"name":"Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki  Helsinki Finland"},{"name":"Department of Cellular Physiology Graduate School of Medical Sciences, Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahid A","family":"Khan","sequence":"additional","affiliation":[{"name":"Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofiia","family":"Olander","sequence":"additional","affiliation":[{"name":"Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Zhaivoron","sequence":"additional","affiliation":[{"name":"Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas 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