Free Fatty Acid Species Differentially Modulate the Inflammatory Gene Response in Primary Human Skeletal Myoblasts

SIMPLE SUMMARY: Epidemiological studies show that obesity increases the risk of muscle mass loss with age, a syndrome called sarcopenic obesity. Obesity leads to increased free fatty acids (FFAs) and excessive fat deposits, which impair the integrity of skeletal muscles by unknown mechanisms. This report indicates that FFAs directly affect human skeletal muscle cell replication and inflammatory gene expression. The structural characteristics of FFAs play a decisive role in triggering both processes. Thus, the characterization of abundant FFA species in the skeletal muscle of obese individuals may become a useful tool to predict the progression of sarcopenic obesity. ABSTRACT: Age-related loss of skeletal muscle is associated with obesity and inflammation. In animal models, intramuscular fat deposits compromise muscle integrity; however, the relevant fat components that mediate muscular inflammation are not known. Previously, we hypothesized that free fatty acids (FFAs) may directly induce inflammatory gene expression in skeletal muscle cells of obese rats. Here, we examined this hypothesis in primary human skeletal myoblasts (SkMs) using multiplex expression analysis of 39 inflammatory proteins in response to different FFA species. Multiplex mRNA quantification confirmed that the IL6, IL1RA, IL4, LIF, CXCL8, CXCL1, CXCL12 and CCL2 genes were differentially regulated by saturated and unsaturated C16 or C18 FFAs. Fluorescence staining revealed that only saturated C16 and C18 strongly interfere with myoblast replication independent of desmin expression, mitochondrial abundance and oxidative activity. Furthermore, we addressed the possible implications of 71 human receptor tyrosine kinases (RTKs) in FFA-mediated effects. Phosphorylated EphB6 and TNK2 were associated with impaired myoblast replication by saturated C16 and C18 FFAs. Our data suggest that abundant FFA species in human skeletal muscle tissue may play a decisive role in the progression of sarcopenic obesity by affecting inflammatory signals or myoblast replication.