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Peer-reviewedCC BY-NCCell reports

Stiffness-Induced Impairment of GLUT4 Trafficking in Adult Cardiomyocytes

  • Alexia Vite1
  • Tony Guo1
  • Nesrine Bouhrira1
  • Deborah M. Eaton1
  • Kenneth C. Bedi1
  • Claire F. Brady1
  • Jonathan J. Edwards1,2
  • Bea Duric1
  • Keita Uchida3
  • Cassidy Olsen1
  • Lola Dong1
  • Benjamin L. Prosser3
2 more authors
  • Zoltan Arany1,3
  • Kenneth B. Margulies1,3,4
4 affiliations
  1. 1Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
  2. 2Department of Pediatrics, Division of Cardiology, Children’s Hospital of Philadelphia, Philadelphia, PA
  3. 3Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
  4. 4Lead Contact
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Abstract

Abnormal myocardial fuel utilization contributes to heart failure (HF). Myocardial glucose uptake in response to insulin is suppressed in patients with HF, but the mechanisms of this metabolic inflexibility are not fully understood. The present studies employ culture surfaces with tunable stiffness, quantitatively mimicking the healthy and diseased heart milieu. We observe that human and rat adult cardiomyocytes cultured on stiff surfaces develop blunted insulin-mediated glucose uptake, associated with intracellular aggregation of the high-affinity glucose transporter GLUT4 within the microtubule network, and with impaired contractility. These effects are prevented by blocking stiffness-induced detyrosination of α-tubulin, and can be partially rescued by metformin, through AMPK activation. Similarly, disabling motor proteins that mediate microtubule-based trafficking of GLUT4 independently alter insulin-mediated glucose uptake and contractility in myocytes. These findings demonstrate a cell-autonomous mechanism of stiffness-induced impairment of GLUT4 trafficking and glucose uptake in adult rat and human cardiomyocytes.

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Cite

BibTeXRIS
BibTeX
@article{vite2026stiffnessinduced,
  title = {{Stiffness-Induced Impairment of GLUT4 Trafficking in Adult Cardiomyocytes}},
  author = {Alexia Vite and Tony Guo and Nesrine Bouhrira and Deborah M. Eaton and Kenneth C. Bedi and Claire F. Brady and Jonathan J. Edwards and Bea Duric and Keita Uchida and Cassidy Olsen and Lola Dong and Benjamin L. Prosser and Zoltan Arany and Kenneth B. Margulies},
  journal = {Cell reports},
  year = {2026},
  month = jun,
  doi = {10.1016/j.celrep.2026.117577},
  url = {https://doi.org/10.1016/j.celrep.2026.117577},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Stiffness-Induced Impairment of GLUT4 Trafficking in Adult Cardiomyocytes
AU  - Alexia Vite
AU  - Tony Guo
AU  - Nesrine Bouhrira
AU  - Deborah M. Eaton
AU  - Kenneth C. Bedi
AU  - Claire F. Brady
AU  - Jonathan J. Edwards
AU  - Bea Duric
AU  - Keita Uchida
AU  - Cassidy Olsen
AU  - Lola Dong
AU  - Benjamin L. Prosser
AU  - Zoltan Arany
AU  - Kenneth B. Margulies
PY  - 2026
DA  - 2026/06/22
JO  - Cell reports
DO  - 10.1016/j.celrep.2026.117577
UR  - https://doi.org/10.1016/j.celrep.2026.117577
AB  - Abnormal myocardial fuel utilization contributes to heart failure (HF). Myocardial glucose uptake in response to insulin is suppressed in patients with HF, but the mechanisms of this metabolic inflexibility are not fully understood. The present studies employ culture surfaces with tunable stiffness, quantitatively mimicking the healthy and diseased heart milieu. We observe that human and rat adult cardiomyocytes cultured on stiff surfaces develop blunted insulin-mediated glucose uptake, associated with intracellular aggregation of the high-affinity glucose transporter GLUT4 within the microtubule network, and with impaired contractility. These effects are prevented by blocking stiffness-induced detyrosination of α-tubulin, and can be partially rescued by metformin, through AMPK activation. Similarly, disabling motor proteins that mediate microtubule-based trafficking of GLUT4 independently alter insulin-mediated glucose uptake and contractility in myocytes. These findings demonstrate a cell-autonomous mechanism of stiffness-induced impairment of GLUT4 trafficking and glucose uptake in adult rat and human cardiomyocytes.
SN  - 2211-1247
ER  -