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 6

The phenotype of tamoxifen-inducible skeletal muscle–specific Piezo1 KO (iM-Piezo1KO) mice.

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The phenotype of tamoxifen-inducible skeletal muscle–specific Piezo1 KO ...
(A–C) Representative images of the lower hind limb, gastrocnemius, and soleus (A), the ratio of gastrocnemius muscle mass to body mass (n = 6 mice) (B), and quantitative RT-PCR analysis of the expression of atrophy-related genes, including Klf15 and Il6, in gastrocnemius (n = 4 mice) (C) for WT or tamoxifen-treated iM-Piezo1KO mice. Scale bars: 2 mm. (D and E) Ratio of muscle mass to body mass (n = 9 mice) (D), and immunoblot analysis of total and phosphorylated (p-) forms of STAT3 in gastrocnemius (n = 6 mice) (E) are shown for WT or iM-Piezo1KO mice subjected to intraperitoneal injection of neutralizing antibodies against IL-6 (0.1 mg/mouse) or control IgG at the onset of tamoxifen treatment. (F and G) Intravital Ca2+ imaging of iM-Piezo1KO/YC3.60–Tg mice. Representative 2-photon images of CFP and YFP fluorescence at a depth of 50 μm from the fascia of the tibialis anterior muscle for tamoxifen-treated iM-YC3.60–Tg mice or iM-Piezo1KO/YC3.60–Tg mice are shown in F. Scale bars: 100 μm (main panels) and 20 μm (insets). Quantitation of the FRET ratio in areas of 6 fibers for each of 3 (iM-YC3.60 Tg) or 4 (iM-Piezo1KO/YC3.60 Tg) hind limbs is shown in G, with white or gray circles or squares indicating the values obtained from individual hind limbs. All quantitative data are mean ± SEM. *P < 0.05, **P < 0.01 by unpaired Student’s t test (B, C, and G) or 2-way ANOVA with Bonferroni’s post hoc test (D and E). NS, not significant.