A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy

J Clin Invest. 2022 May 16;132(10):1-13. doi: 10.1172/JCI154611.


Although immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that Krüppel-like factor 15 (KLF15) and IL-6 are upregulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed Ca2+ bioimaging revealed that the cytosolic Ca2+ concentration ([Ca2+]i) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the downregulation of Piezo1. Acute disruption of Piezo1 in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies against IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated in human samples. Our results thus uncover a paradigm for Ca2+ signaling in that a decrease in [Ca2+]i from the basal level triggers a defined biological event.

Keywords: Calcium signaling; Metabolism; Muscle Biology; Skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Signaling
  • Humans
  • Interleukin-6* / genetics
  • Interleukin-6* / metabolism
  • Ion Channels* / genetics
  • Ion Channels* / metabolism
  • Kruppel-Like Transcription Factors* / genetics
  • Kruppel-Like Transcription Factors* / metabolism
  • Mice
  • Muscle, Skeletal / metabolism
  • Muscular Atrophy* / genetics
  • Muscular Atrophy* / metabolism


  • Interleukin-6
  • Ion Channels
  • Klf15 protein, mouse
  • Kruppel-Like Transcription Factors
  • Piezo1 protein, mouse
  • interleukin-6, mouse
  • Calcium