Piezo1-dependent activation of stromal cells ignites muscle inflammation in exercise and injury and is associated with inflammaging.

As the actuator of movement and a key regulator of organismal metabolism, skeletal muscle is a site at which inflammatory responses must be carefully calibrated to counteract stressors while preventing protracted functional impairments. Exercise, injury and aging are common forms of stress associated with inflammation; yet the specific inducers and sensors driving such inflammation remain poorly characterized. Multipronged assessment of acute and chronic endurance exercise models uncovered a role for muscle mesenchymal stromal cells in transducing exercise-induced mechanical stress into local inflammatory responses and that the mechanosensitive ion channel Piezo1 is the primary molecular sensor. Mechanosensing by stromal cells is also necessary for appropriately timed inflammatory and myogenic responses to acute muscle injury and is associated with age-related muscle inflammation. These findings highlight sensing of altered tissue stiffness by Piezo1 on muscle mesenchymal stromal cells as a fundamental mechanism of stress-induced immunomodulation in skeletal muscle.