Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor.
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.
Program in Genomics, Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, USA.
Fedik
F
Rahimov
Oliver D
OD
King
Leigh C
LC
Warsing
Rachel E
RE
Powell
Charles P
CP
Emerson
Louis M
LM
Kunkel
Kathryn R
KR
Wagner
D030301:Activin Receptors, Type II / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D046228:Microarray Analysis; D018482:Muscle, Skeletal / Q000378:metabolism*; D009135:Muscular Diseases / Q000188:drug therapy / Q000235:genetics; D055435:Myostatin / Q000187:drug effects* / Q000235:genetics*; D052097:Quadriceps Muscle / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D055435:Myostatin; D016212:Transforming Growth Factor beta; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B
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