Advancements in metabolomic and genomic research tools are revealing new insights into how metabolic networks can influence skeletal muscle fiber composition. In this mini-review, we summarize the recent progress of metabolite-dependent signaling pathways and transcriptional regulators that control glycolytic and oxidative metabolism and ultimately influence the type of fibers in muscle depots. These mechanisms expand the role of metabolites beyond that of basic building blocks of cellular components, and illustrate how particular metabolites can take an active role in regulating metabolic homeostasis and fiber adaptation. As new metabolite-dependent mechanisms emerge, ongoing metabolomic studies have begun to help explain why distinct metabolic pathways are used in different biological contexts and widen the view of seminal observations like the Warburg effect.

The amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD)-linked RNA-binding protein called fused in sarcoma (FUS) has been implicated in several aspects of RNA regulation, including mRNA translation. The mechanism by which FUS affects the translation of polyribosomes has not been established. Here we show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian Target of Rapamycin) kinase activity. Specifically, we show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1. Moreover, we report that FUS is necessary for efficient stalling of translation as FUS-deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin1. We also show that ALS-linked FUS mutants, R521G and P525L, associate abundantly with polyribosomes and decrease global protein synthesis. Importantly, the inhibitory effect on translation by FUS is impaired by mutations that reduce its RNA binding affinity. These findings demonstrate that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling, and that ALS-linked FUS-mutants can cause a toxic gain-of-function in the cytoplasm by repressing the translation of mRNA at polyribosomes.

We investigated how endogenous ω-3 PUFA production compared to supplementation could improve obesity-related metabolic dysfunction. Fat-1 transgenic mice, able to endogenously convert exogenous ω-6 to ω-3 PUFA, and their wild-type littermates were fed a high-fat diet and daily gavaged with either ω-3 or ω-6 PUFA-rich oil for 12 weeks. The endogenous production of ω-3 PUFA improved glucose intolerance and insulin resistance but did not affect hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased levels of ω-3 PUFA-containing 2–monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids, in the liver and gastrocnemius muscle, with different impact at molecular species levels, and supplementation of ω-3 PUFAs being more efficacious. Reduced hepatic lipid accumulation was shown to be associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both genetic and supplementation models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice gavaged with ω-3 PUFA also displayed additional changes in the gut microbiota functions with significant reduction of fecal levels of the pro-inflammatory molecules lipopolysaccharide and flagellin. By employing multiple factor analysis, we were able to identify that the metabolic improvements induced by ω-3 PUFA were accompanied by a reduced production of the pro-inflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. In conclusion, while endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, oral ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.