Maladaptive Piezo1 Mechanotransduction Drives Smooth Muscle Aging in the Gut

Aging-related issues in the gastrointestinal system are widespread, yet the underlying causes of the decline in smooth muscle function are still not fully understood. Research has now revealed that the slowing of gut and colon movement, increased stiffness, and reduced muscle contraction seen in aged mice can be attributed to a specific mechanism in smooth muscle cells (SMCs).

By selectively deleting Piezo1 in these cells, researchers were able to restore the youthful movement and force generation previously observed. Conversely, activating Piezo1 in young mice led to symptoms that mirrored the aging-associated transit delays. This pathway was further investigated using single-cell analysis, RNA velocity, stiffness-controlled experiments, and pharmacological interventions.

The findings indicate that increased stiffness contributes to calcium signaling, calcineurin, and nuclear factor of activated T-cells (NFAT) signaling, resulting in the loss of contractile genes. This leads to a remodeling process where synthetic smooth muscle cells take over the function of the aging SMCs, causing the gut wall to stiffen.

Similar patterns were observed in human intestinal SMCs, and individuals with a gain-of-function variant of PIEZO1 exhibited a trend towards slower colonic transit. This research suggests that maladaptive SMC Piezo1 mechanotransduction could be a viable target for interventions aimed at reversing the age-related decline in gut motility.