Kavli Affiliate: David Linden
| Authors: Vikram Joshi, Corey Seavey, Kaitlyn Knutson, Abhilash Sawant, Yasmeen MF Hamed, Mario D’Ambrosio, Emma Laible, Vladimir Dokic, Jason Paul Sinnwell, Yuanhang Liu, Franco F Jin, Colin Thomas, Gwyneth Garramone, Amelia Paul Mazzone, Ferdinando Bonfiglio, Mauro D’Amato, Recep Avci, Peng Du, Madhusudan Grover, Purna C Kashyap, Brooke R Druliner, David R Linden, Gianluca Cipriani, Kara L Marshall, Yongho L Bae, Gianrico Farrugia and Arthur Beyder
| Summary:
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.
Aging alters organ structure, yet how these changes drive functional decline remains poorly defined. We show that progressive stiffening of the gut with age activates the mechanosensitive ion channel Piezo1 in smooth muscle cells, initiating a maladaptive response that impairs contractility and slows intestinal transit. On the other hand, deletion of smooth muscle Piezo1 prevents age-related gut dysmotility. These findings reveal that age-related physical shifts actively drive functional decline through mechanotransduction pathways. By identifying Piezo1 as a critical link between tissue mechanics and organ aging, this work provides a framework for understanding how mechanical cues contribute to age-related dysfunction in the gut and possibly other smooth muscle organs.