Abstract
Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Since skeletal muscle is a major target for insulin, the aim of this study is to explore for the first time the influence of several FAHFAs in C2C12 myoblasts and in skeletal muscle phenotype in mice. Here, we show that eleven FAHFAs belonging to different families inhibit C2C12 myoblast proliferation. In addition, all FAHFAs decreased mitochondrial cytochrome c oxidase activity without affecting reactive oxygen species production and the mitochondrial network. During C2C12 myoblasts differentiation, we found that two of the most active lipids, 9-PAHPA and 9-OAHPA, did not significantly affect the fusion index and the expression of myosin heavy chains. However, we found that three months’ intake of 9-PAHPA or 9-OAHPA in mice increased the expression of more oxidative myosin in skeletal muscle without affecting skeletal muscle mass, number, and mean fiber area, mitochondrial activity, and oxidative stress parameters. In conclusion, our study indicated that the eleven FAHFAs tested decreased the proliferation rate of C2C12 myoblasts, probably through the inhibition of mitochondrial activity. In addition, we found that 9-PAHPA or 9-OAHPA supplementation in mice induced a switch toward a more oxidative contractile phenotype of skeletal muscle. These data suggest that the increase in insulin sensitivity previously described for these two FAHFAs is of muscular origin.
Highlights
The term fatty acid esters of hydroxy fatty acids (FAHFAs) was coined by the Kahn and Sagathelian teams for the fatty acid ester of hydroxy fatty acids that they recently uncovered in white adipose tissues [1]
As we have previously demonstrated that myoblast proliferation could be regulated by mitochondrial activity [16,17,18], this set of data suggests that FAHFAs inhibit C2C12 myoblast proliferation through the inhibition of mitochondrial activity
We investigated the expression of different G-protein-coupled receptors (GPCRs), previously identified to bind and be activated by free fatty acids and/or FAHFAs such as palmitic acid hydroxy stearic acid (PAHSA) [1,4,6,7], to determine if any of them were expressed in proliferative myoblasts
Summary
The term FAHFA was coined by the Kahn and Sagathelian teams for the fatty acid ester of hydroxy fatty acids that they recently uncovered in white adipose tissues [1]. Palmitic acid hydroxy stearic acid (PAHSA) family members, in particular, have been studied, and several works have reported antidiabetic and anti-inflammatory effects [1,2,4,5], suggesting that they could have a high therapeutic potential to prevent and/or to treat type 2 diabetes. Yore et al (2014) demonstrated that acute oral administration of 5-PAHSA in insulin-resistant mice improved glucose tolerance and lowered basal glycemia. Recent work indicates that 5-PAHSA treatment for one month increases insulin resistance and promotes lipid accumulation and inflammatory responses in mice liver [8]. Our work indicated that both 9-PAHPA and 9-OAHPA supplementation increased basal metabolism and enhanced insulin sensitivity in healthy mice [9] and partly counteracted insulin resistance in obese mice [10]
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