Maladaptive Piezo1 Mechanotransduction Drives Smooth Muscle Aging in the Gut

Abstract

Age-related gastrointestinal dysfunction is common, but the mechanisms of aging-associated smooth muscle failure remain unclear. We show that aging in mice slows whole gut and colonic transit, increases regional stiffness, and reduces smooth muscle contractility. Inducible smooth muscle cell (SMC) specific deletion of Piezo1 preserved youthful transit and force generation, whereas Piezo1 activation in young mice phenocopied aging-associated transit delay. Single cell transcriptomics, RNA velocity, stiffness-controlled cell and tissue cultures, and pharmacologic studies revealed that Piezo1 couples increased stiffness to Ca2+, calcineurin, NFAT signaling, loss of contractile gene programs, leading to age-related contractile loss and contractile to synthetic SMC remodeling and gut wall stiffening. Human intestinal SMCs supported conservation of this pathway, and PIEZO1 gain of function carriers showed a trend toward delayed colonic transit. Thus, maladaptive SMC Piezo1 mechanotransduction is a targetable mechanism of aging-associated gut dysmotility.

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BibTeX

@misc{joshi2026maladaptive,
  title = {{Maladaptive Piezo1 Mechanotransduction Drives Smooth Muscle Aging in the Gut}},
  author = {V. Joshi and C. Seavey and K. Knutson and A. Sawant and Y. M. Hamed and M. D'Ambrosio and E. Laible and V. Dokic and J. P. Sinnwell and Y. Liu and F. F. Jin and C. Thomas and G. Garramone and A. P. Mazzone and F. Bonfiglio and M. D'Amato and R. Avci and P. Du and M. Grover and P. C. Kashyap and B. R. Druliner and D. R. Linden and G. Cipriani and K. L. Marshall and Y. L. Bae and G. Farrugia and A. Beyder},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.02.748183},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.02.748183v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Maladaptive Piezo1 Mechanotransduction Drives Smooth Muscle Aging in the Gut
AU  - V. Joshi
AU  - C. Seavey
AU  - K. Knutson
AU  - A. Sawant
AU  - Y. M. Hamed
AU  - M. D'Ambrosio
AU  - E. Laible
AU  - V. Dokic
AU  - J. P. Sinnwell
AU  - Y. Liu
AU  - F. F. Jin
AU  - C. Thomas
AU  - G. Garramone
AU  - A. P. Mazzone
AU  - F. Bonfiglio
AU  - M. D'Amato
AU  - R. Avci
AU  - P. Du
AU  - M. Grover
AU  - P. C. Kashyap
AU  - B. R. Druliner
AU  - D. R. Linden
AU  - G. Cipriani
AU  - K. L. Marshall
AU  - Y. L. Bae
AU  - G. Farrugia
AU  - A. Beyder
PY  - 2026
DA  - 2026/09/02
PB  - bioRxiv
DO  - 10.64898/2026.09.02.748183
UR  - https://www.biorxiv.org/content/10.64898/2026.09.02.748183v1
AB  - Age-related gastrointestinal dysfunction is common, but the mechanisms of aging-associated smooth muscle failure remain unclear. We show that aging in mice slows whole gut and colonic transit, increases regional stiffness, and reduces smooth muscle contractility. Inducible smooth muscle cell (SMC) specific deletion of Piezo1 preserved youthful transit and force generation, whereas Piezo1 activation in young mice phenocopied aging-associated transit delay. Single cell transcriptomics, RNA velocity, stiffness-controlled cell and tissue cultures, and pharmacologic studies revealed that Piezo1 couples increased stiffness to Ca2+, calcineurin, NFAT signaling, loss of contractile gene programs, leading to age-related contractile loss and contractile to synthetic SMC remodeling and gut wall stiffening. Human intestinal SMCs supported conservation of this pathway, and PIEZO1 gain of function carriers showed a trend toward delayed colonic transit. Thus, maladaptive SMC Piezo1 mechanotransduction is a targetable mechanism of aging-associated gut dysmotility.
ER  -

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