The loss of skeletal muscle mass and size, or muscle atrophy, is a common human experience, linked to disability, for which there are no widely accepted pharmacological therapies. Piezo1 is a mechanosensitive cation channel that opens upon alteration of the plasma membrane lipid bilayer, such as through increased membrane tension. In this issue of the JCI, Hirata et al. identified Piezo1 and its downstream effectors, Krüppel-like factor 15 (KLF15) and interleukin-6 (IL-6), as an important signaling pathway in a murine model of disuse atrophy. Through genetic and pharmacological modulation of the pathway, the authors demonstrated that immobilization resulted in downregulation of Piezo1 and basal intracellular calcium concentration ([Ca2+]i), increasing expression of Klf15 and its downstream target Il6 and thereby inducing muscle atrophy. Piezo1 has been considered a therapeutic target for diverse disorders, including atherosclerosis and kidney fibrosis, and with this publication should now also be considered a viable target for disuse atrophy.