Diet-MEF2 Interactions Shape Lipid Droplet Diversification in Muscle to Influence Drosophila Lifespan

The number, size, and composition of lipid droplets can be influenced by dietary changes that shift energy substrate availability. This diversification of lipid droplets can promote metabolic flexibility and shape cellular stress responses in unique tissues with distinctive metabolic roles. Using Drosophila, we uncovered a role for myocyte enhancer-factor 2 (MEF2) in modulating diet-dependent lipid droplet diversification within adult striated muscle, impacting mortality rates. Muscle-specific attenuation of MEF2, whose chronic activation maintains glucose and mitochondrial homeostasis, leads to the accumulation of large, cholesterol ester-enriched intramuscular lipid droplets in response to high calorie, carbohydrate sufficient diets. The diet-dependent accumulation of these lipid droplets also correlates with both enhanced stress protection in muscle and increases in organismal lifespan. Furthermore, MEF2 attenuation releases an antagonistic regulation of cell cycle gene expression programs, and up-regulation of Cyclin E is required for diet-and-MEF2 dependent diversification of intramuscular lipid droplets. The integration of MEF2-regulated gene expression networks with dietary responses thus plays a critical role in shaping muscle metabolism and function, further influencing organismal lifespan. Together, these results highlight a potential protective role for intramuscular lipid droplets during dietary adaptation. Overall design: We wanted to explore MEF-2 dependent muscle transcriptional networks, putatively influenced by carbohydrate availability, that could modulate lipid droplet diversification and potentially alter organismal lifespan. Utilizing transcriptomics (RNA-seq.), we generated genome-wide expression profiles from dissected thoraces of Act88FGS>UAS-MEF2RNAi (+/- RU486) flies fed a high calorie diet (compared to controls [Act88FGS>w1118 +/- RU486]).