Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor

• Published in: Physiological genomics 2011-04, Vol.43 (8), p.398-407
• Main Authors: Rahimov, Fedik, King, Oliver D, Warsing, Leigh C, Powell, Rachel E, Emerson, Jr, Charles P, Kunkel, Louis M, Wagner, Kathryn R
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type II - pharmacology; Animals; Biomarkers - metabolism; Female; Gene Expression - drug effects; Gene Expression Profiling - methods; Mice; Mice, Inbred C57BL; Mice, Knockout - genetics; Microarray Analysis; Muscle, Skeletal - metabolism; Muscular Diseases - drug therapy; Muscular Diseases - genetics; Myostatin - drug effects; Myostatin - genetics; Quadriceps Muscle - drug effects; Quadriceps Muscle - metabolism; Transforming Growth Factor beta - drug effects; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00223.2010

Inhibition of the myostatin signaling pathway is emerging as a promising therapeutic means to treat muscle wasting and degenerative disorders. Activin type IIB receptor (ActRIIB) is the putative myostatin receptor, and a soluble activin receptor (ActRIIB-Fc) has been demonstrated to potently inhibit a subset of transforming growth factor (TGF)-β family members including myostatin. To determine reliable and valid biomarkers for ActRIIB-Fc treatment, we assessed gene expression profiles for quadriceps muscles from mice treated with ActRIIB-Fc compared with mice genetically lacking myostatin and control mice. Expression of 134 genes was significantly altered in mice treated with ActRIIB-Fc over a 2-wk period relative to control mice (fold change > 1.5, P < 0.001), whereas the number of significantly altered genes in mice treated for 2 days was 38, demonstrating a time-dependent response to ActRIIB-Fc in overall muscle gene expression. The number of significantly altered genes in Mstn(-/-) mice relative to control mice was substantially higher (360), but for most of these genes the expression levels in the 2-wk treated mice were closer to the levels in the Mstn(-/-) mice than in control mice (P < 10⁻³⁰). Expression levels of 30 selected genes were further validated with quantitative real-time polymerase chain reaction (qPCR), and a correlation of ≥ 0.89 was observed between the fold changes from the microarray analysis and the qPCR analysis. These data suggest that treatment with ActRIIB-Fc results in overlapping but distinct gene expression signatures compared with myostatin genetic mutation. Differentially expressed genes identified in this study can be used as potential biomarkers for ActRIIB-Fc treatment, which is currently in clinical trials as a therapeutic agent for muscle wasting and degenerative disorders.