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

Muscle mesenchymal stromal cells (MSCs) play a role in transducing exercise-induced mechanical stress into local inflammatory responses.

• Multipronged assessment of acute and chronic endurance exercise models was used to uncover this role.
• MSCs were identified as sensors of altered tissue stiffness in skeletal muscle.
• This stromal cell function was characterized in the context of both acute and chronic exercise paradigms.

Piezo1, a mechanosensitive ion channel, was identified as the primary molecular sensor on muscle mesenchymal stromal cells mediating exercise-induced inflammation.

• Piezo1 is described as 'the primary molecular sensor' in transducing mechanical stress to inflammatory responses.
• The channel operates on muscle mesenchymal stromal cells specifically.
• Piezo1-dependent activation of stromal cells is characterized as 'igniting' muscle inflammation during exercise and injury.

Mechanosensing by stromal cells is necessary for appropriately timed inflammatory and myogenic responses to acute muscle injury.

• Both inflammatory and myogenic responses to acute muscle injury were found to depend on stromal cell mechanosensing.
• The timing of these responses was specifically noted as being regulated by this mechanism.
• Disruption of Piezo1-dependent mechanosensing impaired the proper orchestration of post-injury responses.

Piezo1-dependent mechanosensing by muscle mesenchymal stromal cells is associated with age-related muscle inflammation (inflammaging).

• The paper connects the Piezo1-MSC mechanosensing axis to inflammaging, defined as age-related muscle inflammation.
• Aging is described alongside exercise and injury as a common form of stress associated with inflammation in skeletal muscle.
• The association with inflammaging extends the relevance of this pathway beyond acute stress responses to chronic aging phenotypes.

Exercise, injury, and aging represent common stressors associated with skeletal muscle inflammation, but the specific inducers and sensors had remained poorly characterized prior to this study.

• The authors note that 'the specific inducers and sensors driving such inflammation remain poorly characterized.'
• Skeletal muscle is described as 'the actuator of movement and a key regulator of organismal metabolism.'
• Inflammatory responses in muscle 'must be carefully calibrated to counteract stressors while preventing protracted functional impairments.'

Sensing of altered tissue stiffness by Piezo1 on muscle mesenchymal stromal cells is identified as a fundamental mechanism of stress-induced immunomodulation in skeletal muscle.

• The authors characterize this as 'a fundamental mechanism of stress-induced immunomodulation in skeletal muscle.'
• Tissue stiffness changes are the upstream mechanical signal detected by Piezo1.
• This mechanism unifies the inflammatory responses to multiple distinct stressors including exercise, injury, and aging.