Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor
Wellstone Center for FSHD; Emerson Lab; King Lab
Cell Biology | Developmental Biology | Genetics | 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
Physiol Genomics. 2011 Apr 27;43(8):398-407. doi: 10.1152/physiolgenomics.00223.2010. Epub 2011 Jan 25. Link to article on publisher's site
Rahimov, Fedik; King, Oliver D.; Warsing, Leigh C.; Powell, Rachel E.; Emerson, Charles P. Jr.; 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. 45.