Analysis of human urinary extracellular vesicles reveals disordered renal metabolism in myotonic dystrophy type 1.
| Title: | Analysis of human urinary extracellular vesicles reveals disordered renal metabolism in myotonic dystrophy type 1. |
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| Authors: | Kumari P; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Sullivan LM; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Li Z; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Parker Conquest E; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Cornforth E; School of Health and Rehabilitation Sciences, Massachusetts General Hospital Institute of Health Professions, Boston, MA, USA.; Jayakumar R; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Hu N; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Alexander Sizemore J; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; McKee BB; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Kitchen RR; Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; González-Pérez P; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Linville C; Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.; Castro K; Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA.; Gutierrez H; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.; Samaan S; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.; Townsend EL; School of Health and Rehabilitation Sciences, Massachusetts General Hospital Institute of Health Professions, Boston, MA, USA.; Darras BT; Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.; Rutkove SB; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.; Iannaccone ST; Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA.; Clemens PR; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.; Neurology Section, Veteran's Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.; Puwanant A; Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.; Das S; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. sdas5@mgh.harvard.edu.; Wheeler TM; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. twheeler1@mgh.harvard.edu. |
| Source: | Nature communications [Nat Commun] 2025 Mar 05; Vol. 16 (1), pp. 2158. Date of Electronic Publication: 2025 Mar 05. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Pub. Group |
| MeSH Terms: | Myotonic Dystrophy*/urine ; Myotonic Dystrophy*/metabolism ; Myotonic Dystrophy*/genetics ; Myotonic Dystrophy*/complications ; Myotonic Dystrophy*/pathology ; Kidney*/metabolism ; Kidney*/pathology ; Extracellular Vesicles*/metabolism ; Extracellular Vesicles*/genetics ; Renal Insufficiency, Chronic*/urine ; Renal Insufficiency, Chronic*/metabolism ; Renal Insufficiency, Chronic*/genetics; Biomarkers/urine ; Humans ; Male ; Female ; Middle Aged ; Adult ; Aged |
| Abstract: | Chronic kidney disease (CKD) and the genetic disorder myotonic dystrophy type 1 (DM1) each are associated with progressive muscle wasting, whole-body insulin resistance, and impaired systemic metabolism. However, CKD is undocumented in DM1 and the molecular pathogenesis driving DM1 is unknown to involve the kidney. Here we use urinary extracellular vesicles (EVs), RNA sequencing, droplet digital PCR, and predictive modeling to identify downregulation of metabolism transcripts Phosphoenolpyruvate carboxykinase-1, 4-Hydroxyphenylpyruvate dioxygenase, Dihydropyrimidinase, Glutathione S-transferase alpha-1, Aminoacylase-1, and Electron transfer flavoprotein B in DM1. Expression of these genes localizes to the kidney, especially the proximal tubule, and correlates with muscle strength and function. In DM1 autopsy kidney tissue, characteristic ribonuclear inclusions are evident throughout the nephron. We show that urinary organic acids and acylglycines are elevated in DM1, and correspond to enzyme deficits of downregulated genes. Our study identifies a previously unrecognized site of DM1 molecular pathogenesis and highlights the potential of urinary EVs as biomarkers of renal and metabolic disturbance in these individuals.; (© 2025. The Author(s).) |
| Competing Interests: | Competing interests: M.G.H. and T.M.W. have been awarded a patent (U.S. patent number 11,866,782 B2; International patent application number PCT/2017/043348) for the use of extracellular RNA to identify markers of muscular dystrophies. The remaining authors declare no competing interests. |
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| Grant Information: | K23 NS125110 United States NS NINDS NIH HHS; R61NS117210 U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS); W81XWH-20-1-0293 U.S. Department of Defense (United States Department of Defense); R61 NS117210 United States NS NINDS NIH HHS; 1072634 Muscular Dystrophy Association (Muscular Dystrophy Association Inc.); K23 NS118048 United States NS NINDS NIH HHS; W81XWH-19-1-0392 U.S. Department of Defense (United States Department of Defense) |
| Substance Nomenclature: | 0 (Biomarkers) |
| Entry Date(s): | Date Created: 20250305 Date Completed: 20250511 Latest Revision: 20260307 |
| Update Code: | 20260307 |
| PubMed Central ID: | PMC11882899 |
| DOI: | 10.1038/s41467-025-56479-5 |
| PMID: | 40044661 |
| Database: | MEDLINE |
Journal Article