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.
View: Text | PDF
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

×

Figure 1

Skeletal muscle atrophy triggered by immobilization is prevented in mice with KLF15 deficiency in skeletal muscle.

Options: View larger image (or click on image) Download as PowerPoint
Skeletal muscle atrophy triggered by immobilization is prevented in mice...
(A) Ratio of gastrocnemius or soleus muscle mass in both hind limbs to body mass for control mice or mice subjected to bilateral hind limb immobilization (IM) with a cast for 3 days (n = 18 mice). (B and C) Quantitative RT-PCR analysis of Klf15 mRNA (B) and of atrophy-related gene expression (C) in gastrocnemius of mice as in A (n = 8 mice). (D) Ratio of muscle mass to body mass for WT or M-KLF15KO mice subjected to cast immobilization for 3 days or for corresponding control (Cont) mice (n = 8 mice). (E–G) Hematoxylin-eosin staining (E) for determination of muscle fiber area (F) and the distribution of muscle fiber area (G) in soleus of mice as in D (n = 8 mice). The area of 800 fibers pooled from 4 mice was measured and averaged for each condition in F. Scale bar: 50 μm. (H) Quantitative RT-PCR analysis of atrophy-related gene expression in gastrocnemius of mice as in D (n = 6 mice). Quantitative data are mean ± SEM (A–D, G, and H) or medians (F). *P < 0.05, **P < 0.01 by unpaired Student’s t test (A–C) or 2-way ANOVA with Bonferroni’s post hoc test (D and F–H). NS, not significant.