DHA reduces the atrophy-associated Fn14 protein in differentiated myotubes during coculture with macrophages

Macrophages are an important component of muscle where they are involved in complex processes such as repair, regeneration and hypertrophy. We recently reported that macrophage numbers increase in the muscle of obese patients, suggesting that muscle-resident macrophages could be involved in the development of muscle insulin resistance that is associated with obesity. Coculture of activated macrophages with human muscle cells impairs insulin signaling and induces atrophy signaling pathways in the human muscle cells; this is exacerbated by the addition of palmitic acid. In this study, we tested the hypothesis that docosahexaenoic acid (DHA), a polyunsaturated fatty acid that has anti-inflammatory properties, would have the opposite effect of palmitic acid on muscle-macrophage cocultures. Surprisingly, DHA did not stimulate insulin signaling in human muscle myotubes that were cocultured with fibroblasts or macrophages. However, DHA inhibited Fn14, the TNF-like weak inducer of apoptosis receptor that increases the expression of the muscle-specific ubiquitin ligase MuRF-1 (muscle ring-finger protein-1). DHA treatment also increased the apparent molecular mass of MuRF-1 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels, suggesting that DHA causes MuRF-1 to be posttranslationally modified. In conclusion, these results suggest that DHA may have a beneficial effect on muscle mass in humans by inhibiting the induction of Fn14 by infiltrating macrophages.