Hesperedin promotes MyoD‐induced myogenic differentiation in vitro and in vivo

Abstract

The bioflavonoid, hesperedin, promotes osteoblast differentiation in human mesenchymal stem cells, indicating an anabolic effect of hesperedin on bone metabolism. Murine bone marrow mesenchymal stem cells undergo myogenic differentiation as well as osteogenic differentiation. We therefore explored whether hesperedin modulates muscle cell differentiation. EXPERIMENTAL APPROACHMyoblast C2C12 cells were differentiated into muscle cells in the presence or absence of hesperedin. The effects of hesperedin on myogenic differentiation were determined by analysing specific muscle markers in vitro using reporter gene assays, immunoblotting, RT-PCR and DNA pull-down assays. In vivo, the effects of hesperedin were assessed using the freeze injury-induced muscle regeneration model in mice and daily injections of hesperedin for 6 days. KEY RESULTSHesperedin promoted myogenic differentiation, in a dose-dependent manner, by increasing myogenin gene expression. MyoD-induced myogenin gene transcription was enhanced by hesperedin, as this bioflavonoid augmented the nuclear localization and myogenin promoter-binding of MyoD. In addition, hesperedin increased myogenin and muscle creatine kinase gene expression during myogenic differentiation from C3H10T1/2 mesenchymal stem cells in a MyoD-dependent manner and accelerated in vivo muscle regeneration induced by muscle injury. CONCLUSIONS AND IMPLICATIONSOur results demonstrate that hesperedin promoted myogenic differentiation in vitro and in vivo through activation of MyoD-mediated myogenin expression, suggesting a beneficial role in promoting muscle regeneration, following injury. AbbreviationsMCK, muscle creatine kinase; MEF, myocyte enhancer factor; MHC, myosin heavy chain; DAPI, 4′,6-diamidino-2-phenylindole

Incomplete MyoD-induced transdifferentiation is associated with chromatin remodeling deficiencies

“…Our quantitative approach for analyzing chromatin changes during transdifferentiation, based on classifying genomic regions with different CRLs, also suggests that increasing the nuclear concentration of MyoD or its co-factors could lead to higher CRL scores for myoblast-specific DHS sites. This is consistent with the finding that increasing nuclear localization of MyoD improves reprogramming efficiency ( 70 ). However, increasing MyoD to levels that are not physiologically normal could also lead to off-target binding events and improper reprogramming, as discussed below.…”

Green satsuma mandarin orange (Citrus unshiu) extract reduces adiposity and induces uncoupling protein expression in skeletal muscle of obese mice

“…Although we did not measure the weight of skeletal muscle, it is likely that the restoration of UCP expression and enhancement of lipid metabolism might be the causal factor of enlarged skeletal muscle. Indeed, hesperetin, an aglycone form hesperidin, is proposed to promote myocyte differentiation (Jeong et al, 2011a ), indicating that GME would contribute to enhanced generation and energy metabolism of skeletal muscle. Further studies are required to reveal the effect and action mechanism of GME on muscle metabolism.…”

High throughput screening of mitochondrial bioenergetics in human differentiated myotubes identifies novel enhancers of muscle performance in aged mice

“…Jeong et al . 28 showed that hesperetin improved injury-induced muscle regeneration in vivo via an enhancement of myogenic differentiation. Although we did not examine hesperetin’s effects on myogenic differentiation and regeneration in detail, myogenin and embryonic myosin transcript levels were unchanged after hesperetin treatment in frail mice.…”