A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy
Yu Hirata, … , Hiroaki Wake, Wataru Ogawa
Yu Hirata, … , Hiroaki Wake, Wataru Ogawa
Published March 15, 2022
Citation Information: J Clin Invest. 2022;132(10):e154611. https://doi.org/10.1172/JCI154611.
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Research Article Metabolism Muscle biology

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

Abstract

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.

Authors

Yu Hirata, Kazuhiro Nomura, Daisuke Kato, Yoshihisa Tachibana, Takahiro Niikura, Kana Uchiyama, Tetsuya Hosooka, Tomoaki Fukui, Keisuke Oe, Ryosuke Kuroda, Yuji Hara, Takahiro Adachi, Koji Shibasaki, Hiroaki Wake, Wataru Ogawa

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Figure 5

Effect of a Piezo1 channel activator on immobilization-induced muscle atrophy.

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Effect of a Piezo1 channel activator on immobilization-induced muscle at...
(A) Quantitative RT-PCR analysis of the expression of atrophy-related genes, including Klf15 and Il6, in the tibialis anterior muscle of WT mice at 6 hours after intramuscular injection of Yoda1 (0.2 mg/kg) or vehicle (control) (n = 4 mice). (B and C) Intravital Ca2+ imaging of M-YC3.60–Tg mice. Representative 2-photon images of CFP and YFP fluorescence at the indicated times after intramuscular injection of Yoda1 at 0.2 mg/kg (B) as well as the time course of the FRET ratio (n = 4 mice) (C) are shown for the tibialis anterior of M-YC3.60–Tg mice. Scale bar: 20 μm. (D) Quantitative RT-PCR analysis of the expression of atrophy-related genes, including Klf15 and Il6, in tibialis anterior of control mice or mice subjected to cast immobilization (IM) for 3 days with or without intramuscular injection of Yoda1 (0.2 mg/kg) at the onset of immobilization (n = 8 mice). All quantitative data are mean ± SEM. *P < 0.05, **P < 0.01 by unpaired Student’s t test (A) or 2-way ANOVA with Bonferroni’s post hoc test (D).