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
Affiliations
Iori Sakakibara
Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan; Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan; Department of Nutritional Physiology, Institute of Medical Nutrition, Tokushima University Graduate School, Tokushima 770-8503, Japan
Yuta Yanagihara
Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan; Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Toon, Ehime 791-0295, Japan
Koichi Himori
Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Hokkaido 060-8558, Japan
Takashi Yamada
Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Hokkaido 060-8558, Japan
Hiroshi Sakai
Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan; Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
Yuichiro Sawada
Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan; Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
Hirotaka Takahashi
Division of Cell-Free Sciences, Proteo-Science Center (PROS), Ehime University, Matsuyama, Ehime 790-8577, Japan
Noritaka Saeki
Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan; Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Toon, Ehime 791-0295, Japan
Hiroyuki Hirakawa
Department of Physiology and Cell Biology, Tokyo Medical and Dental University (TMDU), Graduate School, Tokyo 113-8510, Japan
Atsushi Yokoyama
Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
So-ichiro Fukada
Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan
Tatsuya Sawasaki
Division of Cell-Free Sciences, Proteo-Science Center (PROS), Ehime University, Matsuyama, Ehime 790-8577, Japan
Yuuki Imai
Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan; Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan; Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Toon, Ehime 791-0295, Japan; Research Unit for Skeletal Health and Diseases, Ehime University, Toon, Ehime 791-0295, Japan; Corresponding author
Summary: 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.
