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

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Listed:
  • 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
    Veteran’s Affairs Pittsburgh Health Care System)

  • 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)

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.

Suggested Citation

  • 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 Go, 2025. "Analysis of human urinary extracellular vesicles reveals disordered renal metabolism in myotonic dystrophy type 1," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56479-5
    DOI: 10.1038/s41467-025-56479-5
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    References listed on IDEAS

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    1. Mevik, Björn-Helge & Wehrens, Ron, 2007. "The pls Package: Principal Component and Partial Least Squares Regression in R," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 18(i02).
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