Myofiber androgen receptor increases muscle strength mediated by a skeletal muscle splicing variant of Mylk4

Iori Sakakibara; Yuta Yanagihara; Koichi Himori; Takashi Yamada; Hiroshi Sakai; Yuichiro Sawada; Hirotaka Takahashi; Noritaka Saeki; Hiroyuki Hirakawa; Atsushi Yokoyama; So-Ichiro Fukada; Tatsuya Sawasaki; Yuuki Imai

doi:10.1016/j.isci.2021.102303

Myofiber androgen receptor increases muscle strength mediated by a skeletal muscle splicing variant of Mylk4

iScience. 2021 Mar 13;24(4):102303. doi: 10.1016/j.isci.2021.102303. eCollection 2021 Apr 23.

Authors

Iori Sakakibara^{1

2

3}, Yuta Yanagihara^{1

4}, Koichi Himori⁵, Takashi Yamada⁵, Hiroshi Sakai^{1

2}, Yuichiro Sawada^{1

6}, Hirotaka Takahashi⁷, Noritaka Saeki^{1

4}, Hiroyuki Hirakawa⁸, Atsushi Yokoyama⁹, So-Ichiro Fukada¹⁰, Tatsuya Sawasaki⁷, Yuuki Imai^{1

2

4

11}

Affiliations

¹ Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
² Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.
³ Department of Nutritional Physiology, Institute of Medical Nutrition, Tokushima University Graduate School, Tokushima 770-8503, Japan.
⁴ Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Toon, Ehime 791-0295, Japan.
⁵ Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Hokkaido 060-8558, Japan.
⁶ Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.
⁷ Division of Cell-Free Sciences, Proteo-Science Center (PROS), Ehime University, Matsuyama, Ehime 790-8577, Japan.
⁸ Department of Physiology and Cell Biology, Tokyo Medical and Dental University (TMDU), Graduate School, Tokyo 113-8510, Japan.
⁹ Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
¹⁰ Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
¹¹ Research Unit for Skeletal Health and Diseases, Ehime University, Toon, Ehime 791-0295, Japan.

Abstract

Androgens have a robust effect on skeletal muscles to increase muscle mass and strength. The molecular mechanism of androgen/androgen receptor (AR) action on muscle strength is still not well known, especially for the regulation of sarcomeric genes. In this study, we generated androgen-induced hypertrophic model mice, myofiber-specific androgen receptor knockout (cARKO) mice supplemented with dihydrotestosterone (DHT). DHT treatment increased grip strength in control mice but not in cARKO mice. Transcriptome analysis by RNA-seq, using skeletal muscles obtained from control and cARKO mice treated with or without DHT, identified a fast-type muscle-specific novel splicing variant of Myosin light-chain kinase 4 (Mylk4) as a target of AR in skeletal muscles. Mylk4 knockout mice exhibited decreased maximum isometric torque of plantar flexion and passive stiffness of myofibers due to reduced phosphorylation of Myomesin 1 protein. This study suggests that androgen-induced skeletal muscle strength is mediated with Mylk4 and Myomesin 1 axis.

Keywords: Animal Physiology; Endocrinology; Molecular Biology; Molecular Physiology.