DHA but not EPA induces the trans-differentiation of C2C12 cells into white-like adipocytes phenotype

Abstract

Muscle derived stem cells (MDSCs) and myoblast play an important role in myotube regeneration when muscle tissue is injured. However, these cells can be induced to differentiate into adipocytes once exposed to PPARγ activator like EPA and DHA that are highly suggested during pregnancy. The objective of this study aims at determining the identity of trans-differentiated cells by exploring the effect of EPA and DHA on C2C12 undergoing differentiation into brown and white adipocytes. DHA but not EPA committed C2C12 cells reprograming into white like adipocyte phenotype. Also, DHA promoted the expression of lipolysis regulating genes but had no effect on genes regulating β-oxidation referring to its implication in lipid re-esterification. Furthermore, DHA impaired C2C12 cells differentiation into brown adipocytes through reducing the thermogenic capacity and mitochondrial biogenesis of derived cells independent of UCP1. Accordingly, DHA treated groups showed an increased accumulation of lipid droplets and suppressed mitochondrial maximal respiration and spare respiratory capacity. EPA, on the other hand, reduced myogenesis regulating genes, but no significant differences were observed in the expression of adipogenesis key genes. Likewise, EPA suppressed the expression of WAT signature genes indicating that EPA and DHA have an independent role on white adipogensis. Unlike DHA treatment, EPA supplementation had no effect on the differential of C2C12 cells into brown adipocytes. In conclusion, DHA is a potent adipogenic and lipogenic factor that can change the metabolic profile of muscle cells by increasing myocellular fat.

The Effects of Maternal Intake of EPA and DHA Enriched Diet During Pregnancy and Lactation on Offspring’s Muscle Development and Energy Homeostasis

“…Per our knowledge, this the first study investigating the effect of maternal diet enriched with EPA and DHA on fetal muscle development especially during the prenatal stage when de novo myogenesis process is initiated and during early postnatal stage when fully mature myofibers are formed. Our in vivo results were inconsistent with many in vitro studies including our previous ones which referred to the potential differentiation of C2C12 myoblasts into white adipocytes like phenotypes ( Ghnaimawi et al, 2019 ; Hsueh et al, 2018 ; Peng et al, 2012 ; Zhang et al, 2019 ; Lacham-Kaplan et al, 2020 ; Ghnaimawi et al, 2021 ; Ghnaimawi et al, 2020 ). A transient increase in the expression levels of, MtoD1, MRF4, MyoG, and MHC4 was detected in the group fed EPA and DHA enriched diet at D1 ( Figure 3 ) without any change in muscle mass ( Figure 4 ).…”

“…Here, we demonstrated that maternal supplementation of EPA and DHA induced excessive infiltration of intramuscular fat through up-regulation of PPARγ and other adipogenesis regulatory genes. However, the adipogenic effect was not on the expense of myoblasts as having been reported by several in vitro studies ( Peng et al, 2012 ; Hsueh et al, 2018 ; Ghnaimawi et al, 2019 ; Zhang et al, 2019 ; Ghnaimawi et al, 2020 ; Lacham-Kaplan et al, 2020 ; Ghnaimawi et al, 2021 ). Otherwise, it was mediated by PPARγ activation, ectopically expressed in muscle cells.…”

“…In relation to that, some investigations have asserted the beneficial effect of EPA and DHA in enhancing muscle strength and promoting the differentiation process ( Dupont et al, 2019 ; Rodacki et al, 2012 ; Magee et al, 2008 ; Saini et al, 2017 ). Constantly, other studies have reported a negative association between EPA and DHA supplementation and pathways regulating myogenesis and terminal differentiation of myoblasts into mature myotubes ( Ghnaimawi et al, 2019 ; Hsueh et al, 2018 ; Peng et al, 2012 ; Zhang et al, 2019 ; Lacham-Kaplan et al, 2020 ; Ghnaimawi et al, 2021 ; Ghnaimawi et al, 2020 ). Per our knowledge, this the first study investigating the effect of maternal diet enriched with EPA and DHA on fetal muscle development especially during the prenatal stage when de novo myogenesis process is initiated and during early postnatal stage when fully mature myofibers are formed.…”

Comparative Study of Docosahexaenoic Acid with Different Molecular Forms for Promoting Apoptosis of the 95D Non-Small-Cell Lung Cancer Cells in a PPARγ-Dependent Manner

“…Liu et al found that DHA-PC inhibited angiogenesis through activating PPARγ in endothelial cells [ 28 ]. Ghnaimawi et al confirmed that DHA treatment activated PPAR to promote the transdifferentiation of C2C12 cells into adipocyte phenotypes [ 29 ]. Similarly, the cytotoxicity of DHA on many tumor cells is related to the activation of PPARγ.…”