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Open Access | 10.1172/jci.insight.175047
1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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Michele, D.
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1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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Brooks, S.
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1Division of Metabolism, Endocrinology and Diabetes, Department of Internal , University of Michigan, Ann Arbor, United States of America
2Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America
3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America
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Published July 2, 2024 - More info
Pulmonary disorders impact 40% to 80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragmatic weakness. Increased intra-diaphragmatic adiposity and extracellular matrix (ECM) content correlate with reductions in contractile force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein linked with muscular damage in genetic myopathies. THBS1 induces proliferation of fibro-adipogenic progenitors (FAPs) — mesenchymal cells that differentiate into adipocytes and fibroblasts. We hypothesized that THBS1 drives FAP-mediated diaphragm remodeling and contractile dysfunction in DIO. We tested this by comparing the effects of dietary challenge on diaphragms of wild-type (WT) and Thbs1 knockout (Thbs1–/–) mice. Bulk and single-cell transcriptomics demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs displayed upregulation of ECM and TGF β-related expression signatures and augmentation of a Thy1-expressing sub-population previously linked to type 2 diabetes. Despite similar weight gain, Thbs1–/– mice were protected from these transcriptomic changes and from obesity-induced increases in diaphragm adiposity and ECM deposition. Unlike WT controls, Thbs1–/– diaphragms maintained normal contractile force and motion after DIO challenge. These findings establish THBS1 as a necessary mediator of diaphragm stromal remodeling and contractile dysfunction in overnutrition and a potential therapeutic target in obesity-associated respiratory dysfunction.