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

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)12184-12194
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number23
DOIs
Publication statusPublished - Jun 3 2016

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Tando, T., Hirayama, A., Furukawa, M., Sato, Y., Kobayashi, T., Funayama, A., ... Miyamoto, T. (2016). Smad2/3 proteins are required for immobilization-induced skeletal muscle atrophy. Journal of Biological Chemistry, 291(23), 12184-12194. https://doi.org/10.1074/jbc.M115.680579