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

Abstract

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.

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

“…Also, total YAP was increased at 2 days (Fig. 4C), as was the case earlier in mRNA level (47). Because of these changes in the Hippo pathway, we also examined whether the altered Hippo signaling exists after longer myostatin-and activin-blocking treatment.…”

“…sActRIIB-Fc treatment has increased muscle mass and function and has alleviated the disease phenotype in a number of mouse models for neuromuscular disorders (40,45) and in cancer cachexia (68). However, a lack or inhibition of myostatin may decrease oxidative/aerobic capability of muscle (2,37,47,48).…”

“…This occurs at least partially through the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway (27,50,61). A recent microarray study suggested that decreased oxidative capacity occurs after blocking of myostatin and activins by sActRIIB-Fc (47), but no further signaling analysis was conducted. At the moment, the downstream signaling in the myostatin and activin inhibition or blocking situations is not well known (1).…”

Myostatin deficiency is associated with lipidomic abnormalities in skeletal muscles

“…In fact, PPARδ is preferentially found in oxidative rather than glycolytic myofibers [73]. Nevertheless, reduction of oxidative metabolism has been demonstrated using postnatal Mstn inhibition, where fiber type composition was not affected [15,69,77]. Furthermore, no difference has been noted in the percentage of CL in mitochondria from muscles with varying oxidative potentials, as well as in the percent of phospholipid head groups or major fatty acid subclasses [70].…”

Myostatin: genetic variants, therapy and gene doping

“…In order to better demonstrate the underlying mechanisms, forced swimming was performed and ACTRII2B treatment combined with exercise. Finally, it is important to point out that some clinical trials using ACTRIIB are already underway (Rahimov et al, 2011).…”