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 imposed stressors while preventing protracted functional impairments. Exercise, injury, and aging are common forms of stress associated with inflammation, particularly in skeletal muscle, yet the specific inducers and sensors driving such inflammation are not fully understood. Multi-pronged assessment of acute and chronic endurance-exercise models allowed us to evidence a role for MmSCs in transducing exercise-induced mechanical stress into local inflammatory responses. We identified the mechanosensitive ion channel Piezo1 as the molecular sensor of such mechanical stress. We also demonstrated that mechanosensing by stromal cells is necessary for appropriately timed inflammatory and myogenic responses to acute muscle injury and is associated with age-related muscle inflammation. Taken together, these findings highlight recognition of altered tissue stiffness by the Piezo1:MmSC pair as a fundamental mechanism of stress-induced immunomodulation in skeletal muscle.