Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor
Wellstone Center for FSHD
Activin Receptors, Type II; Animals; Biological Markers; Female; Gene Expression; Gene Expression Profiling; Mice; Mice, Inbred C57BL; Mice, Knockout; Microarray Analysis; Muscle, Skeletal; Muscular Diseases; Myostatin; Quadriceps Muscle; Transforming Growth Factor beta
Cell Biology | Developmental Biology | Molecular Biology | Molecular Genetics | Musculoskeletal Diseases | Nervous System Diseases
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)-beta 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(-)(3)(0)). 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.
DOI of Published Version
Rahimov F, King OD, Warsing LC, Powell RE, Emerson CP Jr, Kunkel LM, Wagner KR. Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor. Physiol Genomics. 2011 Apr 27;43(8):398-407. doi:10.1152/physiolgenomics.00223.2010.Link to article on publisher's site
Rahimov, Fedik; King, Oliver D.; Warsing, Leigh C.; Powell, Rachel E.; Emerson, Jr., Charles P.; Kunkel, Louis M.; and Wagner, Kathryn R., "Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor" (2011). Wellstone Center for FSHD Publications. 15.