Smad2 and Smad3 expressed in skeletal muscle promote immobilization-induced bone atrophy in mice

• Published in: Biochemical and biophysical research communications 2021-12, Vol.582, p.111-117
• Main Authors: Umezu, Taro, Nakamura, Satoshi, Sato, Yuiko, Kobayashi, Tami, Ito, Eri, Abe, Takaya, Kaneko, Mari, Nomura, Masatoshi, Yoshimura, Akihiko, Oya, Akihito, Matsumoto, Morio, Nakamura, Masaya, Kanaji, Arihiko, Miyamoto, Takeshi
• Format: Article
• Language: English
• Subjects: Animals; Atrophy; Bone; Crosses, Genetic; Female; Gene Expression Regulation; Immobilization; Integrases - genetics; Integrases - metabolism; Male; Mice; Mice, Knockout; Muscle Denervation - methods; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - innervation; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Muscular Atrophy - prevention & control; Sciatic Nerve - injuries; Signal Transduction; Skeletal muscle; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; Smad2; Smad2 Protein - deficiency; Smad2 Protein - genetics; Smad3; Smad3 Protein - deficiency; Smad3 Protein - genetics; Tibia - innervation; Tibia - metabolism; Tripartite Motif Proteins - genetics; Tripartite Motif Proteins - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.10.043

Skeletal muscle is known to regulate bone homeostasis through muscle-bone interaction, although factors that control this activity remain unclear. Here, we newly established Smad3-flox mice, and then generated skeletal muscle-specific Smad2/Smad3 double conditional knockout mice (DcKO) by crossing Smad3-flox with skeletal muscle-specific Ckmm Cre and Smad2-flox mice. We show that immobilization-induced gastrocnemius muscle atrophy occurring due to sciatic nerve denervation was partially but significantly inhibited in DcKO mice, suggesting that skeletal muscle cell-intrinsic Smad2/3 is required for immobilization-induced muscle atrophy. Also, tibial bone atrophy seen after sciatic nerve denervation was partially but significantly inhibited in DcKO mice. Bone formation rate in wild-type mouse tibia was significantly inhibited by immobilization, but inhibition was abrogated in DcKO mice. We propose that skeletal muscle regulates immobilization-induced bone atrophy via Smad2/3, and Smad2/3 represent potential therapeutic targets to prevent both immobilization-induced bone and muscle atrophy. •Smad3 flox mice were newly established.•Skeletal muscle specific Smad2/3 conditional knockout (Smad2/3 cKO) were generated.•Smad2/3 cKO are resistant to denervation induced muscle and bone atrophy.•Denervation induced bone atrophy is promoted by Smad2/3 in muscles.