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Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Forty\u2010six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the <jats:italic>vastus lateralis<\/jats:italic> were assayed for fibre\u2010type distribution and cross\u2010sectional area via immunofluorescence microscopy and RNA\u2010sequenced to generate transcriptome\u2010wide gene expression data. Sex\u2010stratified <jats:italic>k<\/jats:italic>\u2010means clustering of type I and IIx\/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co\u2010expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Abnormal myofibre proportion was defined in males with COPD (<jats:italic>n<\/jats:italic>\u00a0=\u00a029) as &lt;18% type I and\/or &gt;22% type IIx\/IIax fibres and in females with COPD (<jats:italic>n<\/jats:italic>\u00a0=\u00a017) as &lt;36% type I and\/or &gt;12% type IIx\/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0\u00a0kg, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.022), 6\u2010min walk distance (300 vs. 353\u00a0m, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.039) and forced expiratory volume in 1\u00a0s\u2010to\u2010forced vital capacity ratio (0.42 vs. 0.48, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.041) compared with participants with COPD and normal myofibre proportions. Twenty\u2010nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated <jats:italic>NEB<\/jats:italic>, <jats:italic>TPM1<\/jats:italic> and <jats:italic>TPM2<\/jats:italic> genes having the largest fold differences. Co\u2010expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co\u2010expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co\u2010expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13473","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T03:15:18Z","timestamp":1713842118000},"page":"1016-1029","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Differentially co\u2010expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9935-6319","authenticated-orcid":false,"suffix":"III","given":"Joe W.","family":"Chiles","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ava C.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham  Birmingham AL USA"},{"name":"Department of Epidemiology, School of Public Health University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Tindal","sequence":"additional","affiliation":[{"name":"School of Medicine University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaleen","family":"Lavin","sequence":"additional","affiliation":[{"name":"Florida Institute for Human &amp; Machine Cognition  Pensacola FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Windham","sequence":"additional","affiliation":[{"name":"Division of Trauma and Acute Care Surgery, Department of Surgery University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry B.","family":"Rossiter","sequence":"additional","affiliation":[{"name":"Institute of Respiratory Medicine and Exercise Physiology Lundquist Institute for Biomedical Innovation at Harbor\u2014UCLA Medical Center  Torrance CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Casaburi","sequence":"additional","affiliation":[{"name":"Institute of Respiratory Medicine and Exercise Physiology Lundquist Institute for Biomedical Innovation at Harbor\u2014UCLA Medical Center  Torrance CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Thalacker\u2010Mercer","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology University of Alabama at Birmingham  Birmingham AL USA"},{"name":"Birmingham\/Atlanta Geriatric Research Education and Clinical Center Birmingham Veterans Affairs Medical Center  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"Buford","sequence":"additional","affiliation":[{"name":"Birmingham\/Atlanta Geriatric Research Education and Clinical Center Birmingham Veterans Affairs Medical Center  Birmingham AL USA"},{"name":"Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Michael","family":"Wells","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham  Birmingham AL USA"},{"name":"Birmingham Veterans Affairs Healthcare System  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcas M.","family":"Bamman","sequence":"additional","affiliation":[{"name":"Florida Institute for Human &amp; Machine Cognition  Pensacola FL USA"},{"name":"Department of Cell, Developmental, and Integrative Biology University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz Y.","family":"Hanaoka","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Oklahoma Health Sciences Center  Oklahoma City OK 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