Analysis of human urinary extracellular vesicles reveals disordered renal metabolism in myotonic dystrophy type 1

Preeti Kumari, Lauren M. Sullivan, Zhaozhi Li, E. Parker Conquest, Elizabeth Cornforth, Rojashree Jayakumar, Ningyan Hu, J. Alexander Sizemore, Brigham B. McKee, Robert R. Kitchen, Paloma González-Pérez, Constance Linville, Karla Castro, Hilda Gutierrez, Soleil Samaan, Elise L. Townsend, Basil T. Darras, Seward B. Rutkove, Susan T. Iannaccone, Paula R. Clemens, Araya Puwanant, Sudeshna Das () and Thurman M. Wheeler ()
Additional contact information
Preeti Kumari: Massachusetts General Hospital and Harvard Medical School
Lauren M. Sullivan: Massachusetts General Hospital and Harvard Medical School
Zhaozhi Li: Massachusetts General Hospital and Harvard Medical School
E. Parker Conquest: Massachusetts General Hospital and Harvard Medical School
Elizabeth Cornforth: Massachusetts General Hospital Institute of Health Professions
Rojashree Jayakumar: Massachusetts General Hospital and Harvard Medical School
Ningyan Hu: Massachusetts General Hospital and Harvard Medical School
J. Alexander Sizemore: Massachusetts General Hospital and Harvard Medical School
Brigham B. McKee: Massachusetts General Hospital and Harvard Medical School
Robert R. Kitchen: Massachusetts General Hospital and Harvard Medical School
Paloma González-Pérez: Massachusetts General Hospital and Harvard Medical School
Constance Linville: Wake Forest University School of Medicine
Karla Castro: University of Texas Southwestern
Hilda Gutierrez: Beth Israel Deaconess Medical Center and Harvard Medical School
Soleil Samaan: Beth Israel Deaconess Medical Center and Harvard Medical School
Elise L. Townsend: Massachusetts General Hospital Institute of Health Professions
Basil T. Darras: Boston Children’s Hospital and Harvard Medical School
Seward B. Rutkove: Beth Israel Deaconess Medical Center and Harvard Medical School
Susan T. Iannaccone: University of Texas Southwestern
Paula R. Clemens: University of Pittsburgh
Araya Puwanant: Wake Forest University School of Medicine
Sudeshna Das: Massachusetts General Hospital and Harvard Medical School
Thurman M. Wheeler: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56479-5

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