Brain and Muscle Arnt-like 1 is a Key Regulator of Myogenesis

Abstract

SummaryThe circadian clock network is an evolutionarily conserved mechanism that imparts temporal regulation to diverse biological processes. Brain and muscle Arnt-like 1 (Bmal1), an essential transcriptional activator of the clock, is highly expressed in skeletal muscle. However, whether this key clock component impacts myogenesis, a temporally regulated event that requires the sequential activation of myogenic regulatory factors, is not known. Here we report a novel function of Bmal1 in controlling myogenic differentiation through direct transcriptional activation of components of the canonical Wnt signaling cascade, a major inductive signal for embryonic and postnatal muscle growth. Genetic loss of Bmal1 in mice leads to reduced total muscle mass and Bmal1-deficient primary myoblasts exhibit significantly impaired myogenic differentiation accompanied by markedly blunted expression of key myogenic regulatory factors. Conversely, forced expression of Bmal1 enhances differentiation of C2C12 myoblasts. This cell-autonomous effect of Bmal1 is mediated by Wnt signaling as both expression and activity of Wnt components are markedly attenuated by inhibition of Bmal1, and activation of the Wnt pathway partially rescues the myogenic defect in Bmal1-deficient myoblasts. We further reveal direct association of Bmal1 with promoters of canonical Wnt pathway genes, and as a result of this transcriptional regulation, Wnt signaling components exhibit intrinsic circadian oscillation. Collectively, our study demonstrates that the core clock gene, Bmal1, is a positive regulator of myogenesis, which may represent a temporal regulatory mechanism to fine-tune myocyte differentiation.

Circadian clock-mediated control of stem cell division and differentiation: beyond night and day

“…The converse occurred upon Bmal1 overexpression. An inversed role has been ascribed to Bmal1 in the case of myogenesis: here, knockout of Bmal1 led to reduced muscle mass and blunted expression of key myogenic regulators, presumably due to circadian control of WNT pathway activity (Chatterjee et al, 2013). Bmal1 deficiency is also linked to reduced osteoblast proliferation in adult mice, although a circadian role here has not been proven .…”

The adipocyte clock controls brown adipogenesis via TGF-β/BMP signaling pathway

“…Total protein (40-50 mg) was used for the analysis as described previously (Chatterjee et al, 2013). Smad2, Smad3 or Smad1/5 and p38 phosphorylation were assessed at 1 hour after the indicated ligand treatment (TGF-b1, 10 ng/ml; BMP7 100 ng/ml).…”

“…Immunoprecipitation was performed using Bmal1 (AB93806) or control rabbit IgG plus Protein A/G beads as described previously (Chatterjee et al, 2013). Briefly, cells were fixed with formaldehyde, lysed and sonicated to shear the chromatin.…”

“…By contrast, it potently promotes myogenic progression in skeletal muscle (Chatterjee et al, 2013). As BAT shares a common mesodermal origin with WAT and skeletal muscle, in the current study, we investigated whether Bmal1 participates in brown adipocyte development.…”

Pulmonary and hemostatic toxicity of multi-walled carbon nanotubes and zinc oxide nanoparticles after pulmonary exposure in Bmal1 knockout mice

“…Additional to the role of the Bmal1 gene in the cardiovascular system, the Bmal1 −/− mouse model previously has been used for research regarding osteogenesis, myogenesis, insulin resistance and obesity [23][24][25].…”