An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy

• Published in: Laboratory investigation Vol. 92; no. 8; pp. 1100 - 1114
• Main Authors: Ohsawa, Yutaka, Okada, Tadashi, Nishimatsu, Shin-ichiro, Ishizaki, Masatoshi, Suga, Tomohiro, Fujino, Masahiro, Murakami, Tatsufumi, Uchino, Makoto, Tsuchida, Kunihiro, Noji, Sumihare, Hinohara, Atsushi, Shimizu, Toshiyuki, Shimizu, Kiyoshi, Sunada, Yoshihide
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.08.2012; Nature Publishing Group US; Nature Publishing Group
• Subjects: 692/699/375/374; 692/700/565/1436/2185; Activin Receptors, Type I - antagonists & inhibitors; Activin Receptors, Type I - pharmacology; Activins - metabolism; Activins - pharmacology; Animals; Biological and medical sciences; Biotechnology; caveolin 3; Caveolin 3 - deficiency; Caveolin 3 - genetics; Caveolin 3 - metabolism; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Line; Disease Models, Animal; Diseases of striated muscles. Neuromuscular diseases; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; HEK293 Cells; Humans; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; limb-girdle muscular dystrophy 1C; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Muscle Development - drug effects; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; muscular atrophy; Muscular Dystrophies, Limb-Girdle - drug therapy; Muscular Dystrophies, Limb-Girdle - metabolism; Muscular Dystrophies, Limb-Girdle - pathology; myoblast; Myoblasts - pathology; Myostatin - metabolism; Myostatin - pharmacology; Neurology; Pathology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta - antagonists & inhibitors; research-article; satellite cell; Satellite Cells, Skeletal Muscle - drug effects; Signal Transduction; small-molecule kinase inhibitor; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; transforming growth factor-β type I receptor kinase; caveolin 3; satellite cell; small-molecule kinase inhibitor; myoblast; muscular atrophy; limb-girdle muscular dystrophy 1C; transforming growth factor-β type I receptor kinase; type I receptor kinase; transforming growth factor; Biotechnology; Animal model; Membrane protein; Transforming growth factor β; Muscular dystrophy; Atrophy; Molecules; Clinical biology; Satellite cell; Biological receptor; Nervous system diseases; Neuromuscular diseases; Enzyme; Amyotrophy; Caveolin; Transferases; Deficiency; Rodentia; limb-girdle muscular dystrophy 1 C; Genetic disease; Striated muscle disease; Vertebrata; Mammalia; Mouse; Kinase; Myoblast; Limb girdle muscular dystrophy; Inhibitor; Transforming growth factor β receptor 1
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2012.78

Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3P104L) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-β) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-β type I receptor (TβRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-β1, -β2, and -β3 signaling. Here, we show that a TβRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-β1, as well as CAV3P104L. Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3P104L mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-β family members in muscle. These data indicate that both TGF-β-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TβRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-β signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings.