Polyunsaturated Fatty Acids Prevent Myosteatosis and Lipotoxicity

Myosteatosis occurs in response to excess circulating fatty acids and is associated with muscle dysfunction. This study aimed to characterize the sequence of events of lipid-induced toxicity within muscle cells and the role of polyunsaturated fatty acids (PUFA) as potential preventive factors. Myosteatosis was induced in C2C12 myotubes exposed to palmitic acid (PAL 500μM). Furthermore, cells were co-incubated with PUFA (α-linolenic acid = ALA, Eicosapentaenoic acid = EPA, Docosahexaenoic acid = DHA; Arachidonic acid = ARA) over a period of 48 hours. Cell viability, morphology, and measures of lipid and protein metabolism were assessed at 6, 12, 24, and 48 hours. We observed that myotube integrity was rapidly and progressively disrupted by PAL treatment after 12 hours, ultimately leading to cell death (41.7% cell survival at 48 hours, p<0.05). Cell death did not occur in cells exposed to PAL+ARA and PAL+DHA. After six hours of PAL treatment, an accumulation of large lipid droplets was observed within the cell (6 folds, p<0.05). This was associated with an increase in ceramides (CER x3 fold change) and diacylglycerol (DAG x150 fold change) contents (p<0.05). At the same time, insulin was no longer able to stimulate protein synthesis (p<0.05) nor leverage autophagic flux (p<0.05). DHA and ARA were able to completely reverse the defect in protein synthesis and partially modulate the accumulation of CER and DAG. These findings present new and intriguing research avenues in the field of muscle metabolism and nutrition, particularly in the context of aging, chronic muscle disorders, and insulin resistance.