Abstract
Sarcopenic obesity is characterised by high fat mass, low muscle mass and an elevated inflammatory environmental milieu. We therefore investigated the effects of elevated inflammatory cytokine TNF-α (aging/obesity) and saturated fatty acid, palmitate (obesity) on skeletal muscle cells in the presence/absence of EPA, a-3 polyunsaturated fatty acid with proposed anti-inflammatory, anti-obesity activities. In the present study we show that palmitate was lipotoxic, inducing high levels of cell death and blocking myotube formation. Cell death under these conditions was associated with increased caspase activity, suppression of differentiation, reductions in both creatine kinase activity and gene expression of myogenic factors; IGF-II, IGFBP-5, MyoD and myogenin. However, inhibition of caspase activity via administration of Z-VDVAD-FMK (caspase-2), Z-DEVD-FMK (caspase-3) and ZIETD-KMK (caspase 8) was without effect on cell death. By contrast, lipotoxicity associated with elevated palmitate was reduced with the MEK inhibitor PD98059, indicating palmitate induced cell death was MAPK mediated. These lipotoxic conditions were further exacerbated in the presence of inflammation via TNF-α co-administration. Addition of EPA under cytotoxic stress (TNF-α) was shown to partially rescue differentiation with enhanced myotube formation being associated with increased MyoD, myogenin, IGF-II and IGFBP-5 expression. EPA had little impact on the cell death phenotype observed in lipotoxic conditions but did show benefit in restoring differentiation under lipotoxic plus cytotoxic conditions. Under these conditions Id3 (inhibitor of differentiation) gene expression was inversely linked with survival rates, potentially indicating a novel role of EPA and Id3 in the regulation of apoptosis in lipotoxic/cytotoxic conditions. Additionally, signalling studies indicated the combination of lipo- and cyto-toxic effects on the muscle cells acted through ceramide, JNK and MAPK pathways and blocking these pathways using PD98059 (MEK inhibitor) and Fumonisin B1 (ceramide inhibitor) significantly reduced levels of cell death. These findings highlight novel pathways associated with in vitro models of lipotoxicity (palmitate-mediated) and cytotoxicity (inflammatory cytokine mediated) in the potential targeting of molecular modulators of sarcopenic obesity.
Highlights
The two greatest epidemiological trends of modern times are the rapidly advancing age of the worldwide population and the obesity epidemic
Palmitate increases cell death and reduces differentiation, which is improved with eicosapentaenoic acid (EPA) administration
Initial experiments assessed the effects of EPA (50 lM) and palmitate (750 lM) on C2 skeletal muscle cells
Summary
The two greatest epidemiological trends of modern times are the rapidly advancing age of the worldwide population and the obesity epidemic. Ageing is accompanied by changes in body composition characterised by a relative decline in muscle mass (Aniansson et al 1983) and an increase in fat mass (Lara-Castro et al 2002), a condition termed sarcopenic obesity (SO) (Roubenoff 2004; Zamboni et al 2008). The prevalence of sarcopenic obesity is thought to account for 25% of the population aged over 60 (Batsis et al 2016) with a greater prevalence reported in men (42.9%) than women (18.1%) (Batsis et al 2014). Excess adiposity and reduced muscle mass lead to adverse metabolic effects (e.g., hypertension, dyslipidaemia, insulin resistance). A combination of increased adiposity and reduced lean mass, engendered by ageing, may contribute further to the worsening of metabolic impairments. The combination of low muscle mass and strength with obesity are further associated with a pro-inflammatory
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