{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T14:12:08Z","timestamp":1779804728338,"version":"3.53.1"},"reference-count":40,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China Fundamental Research Funds for the Central Universities","award":["2026063"],"award-info":[{"award-number":["2026063"]}]},{"name":"China Fundamental Research Funds for the Central Universities","award":["2025KYPT05"],"award-info":[{"award-number":["2025KYPT05"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Physical inactivity contributes to type 2 diabetes (T2D), but the molecular links between exercise and metabolic improvement remain incompletely understood. We meta-analyzed genome-wide association studies of vigorous physical activity and T2D (combined n \u2248 1.95 million) and integrated eQTL\/sQTL maps with single-cell and spatial transcriptomic datasets to connect genetic risk with tissues, cell types, and regulatory programs. Tissue and cell-type enrichment, colocalization, and network analyses were performed. Computational findings were further examined in male 10-week-old C57BL\/6J mice with high-fat diet-induced diabetes. After 1 week of acclimatization, mice were randomly assigned to normal chow, high-fat diet, or high-fat diet plus exercise groups (n = 6 per group; high-fat diet with 60% of total energy from fat). The exercise intervention consisted of treadmill running (10 m\/min for 50 min per day, 5 days per week, total 16 weeks), followed by metabolic phenotyping, skeletal muscle histology, bulk RNA sequencing, alternative splicing analysis, and RT-qPCR of Mau2 isoforms. Exercise- and T2D-associated variants showed joint enrichment in skeletal muscle and adipose eQTL\/sQTL signals. Integrated single-cell analyses prioritized fibro-adipogenic progenitors and endothelial cells, and identified an extracellular matrix- and collagen-related module in fibro-adipogenic progenitors associated with both exercise and T2D. Mau2 emerged as a shared candidate gene with tissue-specific splicing signals. In diabetic mice, exercise improved glucose homeostasis and muscle fiber structure, and reduced Mau2 intron retention in skeletal muscle without changing total Mau2 expression. These findings support a multiscale framework linking exercise-responsive regulation to T2D-related tissue remodeling and splicing plasticity.<\/jats:p>","DOI":"10.3390\/cells15110979","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T13:28:21Z","timestamp":1779802101000},"page":"979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Multi-Omics Analysis Identifies Tissue, Cellular and Splicing Programs Associated with Exercise-Mediated Improvement in Type 2 Diabetes"],"prefix":"10.3390","volume":"15","author":[{"given":"Jingzhe","family":"Xiao","sequence":"first","affiliation":[{"name":"China Ice Sport College, Beijing Sport University, Beijing 100084, China"},{"name":"Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Ding","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songbo","family":"Li","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1268-8292","authenticated-orcid":false,"given":"Ziyue","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6706-375X","authenticated-orcid":false,"given":"Pengyu","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Physical Education, Northwestern Polytechnical University, Xi\u2019an 710072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9080-1471","authenticated-orcid":false,"given":"Chunyan","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"},{"name":"Beijing Sports Nutrition Engineering Research Center, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3502-0901","authenticated-orcid":false,"given":"Lijing","family":"Gong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China"},{"name":"Key Laboratory for Performance Training & Recovery of General Administration of Sport, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1152\/physrev.00022.2022","article-title":"Physiology of sedentary behavior","volume":"103","author":"Pinto","year":"2023","journal-title":"Physiol. 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