FAHFAs Regulate the Proliferation of C2C12 Myoblasts and Induce a Shift toward a More Oxidative Phenotype in Mouse Skeletal Muscle

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.

Potential physio-pathological effects of branched fatty acid esters of hydroxy fatty acids

“…In mice fed with a control diet or supplemented with 9-PAHPA or 9-OAHPA for 12 weeks, both these FAHFAs increased basal metabolism and insulin sensitivity, but without modifying glucose tolerance [13]. Our data also showed that this insulin-sensitive effect was probably exerted at the skeletal muscle level [67]. However, 9-PAHPA intake and to a lesser extent 9-OAHPA intake induced liver steatosis and fibrosis in some healthy mice.…”

“…To date, as discussed below, the PAHSA family is the most studied. However, the effects of omega-3 fatty acid FAHFAs (DHAHLA and EPAHSA families) [4,32], omega-6 fatty acid derived FAHFAs (several LAHLAs) [66], and two FAHFAs differing only in the length and saturation of the fatty acid chain (9-PAHPA and 9-OAHPA) [12,13,67] were also investigated.…”

Distinct biological activities of isomers from several families of branched fatty acid esters of hydroxy fatty acids (FAHFAs)

“…Recently, an increasing number of FAHFA families and hundreds of regioisomers have been identified in humans, animals, and plants ( 7 , 8 , 9 , 11 ). However, the biological functions of only a few FAHFA family members have been reported ( 7 , 13 , 14 , 16 , 20 , 21 , 22 , 23 , 27 , 37 , 38 , 39 , 40 ). We sought to determine whether different isomers within the same FAHFA family and whether FAHFAs from different families have similar biological effects.…”

Potential favourable health effects of some dietary uncommon fatty acids

“…9-PAHPA or 9-OAHPA increased insulin sensitivity, but without modifying glucose tolerance, and increased basal metabolism, both in healthy mice and in obese mice with lower insulin sensitivity (Benlebna et al, 2020a(Benlebna et al, , 2020b. Moreover, 9-PAHPA or 9-OAHPA induced a switch toward a more oxidative contractile phenotype of skeletal muscle, suggesting a muscular origin of the increase in insulin sensitivity observed (Benlebna et al, 2020c). Surprisingly, 9-PAHPA or 9-OAHPA induced hepatic steatosis and fibrosis in some healthy mice but not in obese mice, likely because both FAHFAs had insulinsensitized the healthy liver so much that de novo lipogenesis promoted steatosis/fibrosis (Benlebna et al, 2020a(Benlebna et al, , 2020b.…”

“…Acknowledgement. The authors acknowledge the financial support of the French Lipid Nutrition Group for the work conducted on 9-PAHPA and 9-OAHPA (Benlebna et al, 2020a(Benlebna et al, , 2020b(Benlebna et al, , 2020c. We thank all colleagues who have contributed and/or who are co-authors of our publications cited in this review.…”