Smad2/3 proteins are required for immobilization-induced skeletal muscle atrophy

Toshimi Tando, Akiyoshi Hirayama, Mitsuru Furukawa, Yuiko Sato, Tami Kobayashi, Atsushi Funayama, Arihiko Kanaji, Wu Hao, Ryuichi Watanabe, Mayu Morita, Takatsugu Oike, Kana Miyamoto, Tomoyoshi Soga, Masatoshi Nomura, Akihiko Yoshimura, Masaru Tomita, Morio Matsumoto, Masaya Nakamura, Yoshiaki Toyama, Takeshi Miyamoto

研究成果: Article査読

37 被引用数 (Scopus)

抄録

Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes.

本文言語English
ページ(範囲)12184-12194
ページ数11
ジャーナルJournal of Biological Chemistry
291
23
DOI
出版ステータスPublished - 2016 6月 3

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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