Piezo1 Regulates the Skeletal Muscle Length–Tension Relationship Through Channel-Independent Mechanotransduction

Piezo1 mechanosensitive ion channels convert mechanical stimuli into biochemical signals across diverse tissues, yet their role in the contractile function of adult skeletal muscle remains unclear. Here, we demonstrate that Piezo1 regulates skeletal muscle mechanics through a channel-independent mechanism that tunes the length-tension relationship. We examined the effects of pharmacological modulation using the Piezo1 agonist Yoda1 and antagonist Dooku1 in individual muscle fibers from wild-type mice and from muscles with reduced Piezo1 expression (anti-Piezo1 shRNA) using calcium influx and electrophysiological assays. Ex vivo force measurements were performed on these muscles and compared with the dystrophic mdx model. Piezo1 activation had no effect on force at resting length, whereas its inhibition significantly reduced contractile force at stretched lengths, indicating a selective role in length-dependent force regulation. This effect was independent of extracellular calcium and diminished by Piezo1 knockdown. This reduction was absent in mdx muscle, demonstrating dependence on an intact dystrophin-associated cytoskeleton. These findings identify Piezo1 as a previously unrecognized regulator of muscle mechanical performance that operates independently of ion conduction. Our results uncover a mechanobiological interface between Piezo1 and cytoskeletal integrity, expanding current concepts of muscle mechanoregulation and highlighting Piezo1 as a potential therapeutic target for improving muscle function.