Growth differentiation factor 10 inhibits fat infiltration in tongue muscles of mice with high-fat diet

Background: Tongue muscles contain a much greater number of residual adipocytes than other muscles do, which makes them susceptible to obesity-induced muscle fat remodeling. Tongue fat remodeling leads to obesity-induced obstructive sleep apnea (OSA), which is a common sleep disorder characterized by repeated episodes of upper airway collapse during sleep, resulting in fragmented sleep and oxygen deprivation. Although the obstructive role of fat remodeling in tongue muscles for OSA has been confirmed, the cellular and molecular mechanisms regulating fat remodeling in tongue and its impact on tongue muscles have not been well explored. Methods: To study the impact of obesity on adipocytes and neuromuscular junctions (NMJs) in tongue muscles, we used a high-fat diet (HFD)-induced obese preclinical model. Results: The results demonstrated hypertrophy of adipocytes and denervation at NMJs in tongue muscles by a HFD. Mechanistically, we revealed that a HFD repressed the expression of growth differentiation factor 10 (GDF10), which is expressed mainly in fibroadipogenic progenitors (FAPs) in skeletal muscles, repressing adipogenesis and maintaining the integrity of neuromuscular connections. We identified sex differences and muscle specificity of Gdf10 mRNA expression in FAPs. To understand how a HFD significantly reduces the level of Gdf10 mRNA expression in FAPs of the tongue, we investigated the epigenetic regulation of Gdf10. We found that a HFD increases miR-144-3p in tongue FAPs, which interferes with Gdf10 mRNA expression and induces adipogenesis. GDF10 overexpression by viral delivery effectively prevented HFD-induced fat remodeling of tongue and limb muscles. Conclusion: These findings provide important insight into the role of FAP-derived GDF10 in the interplay between fat contents and tongue muscles in response to obesity and suggest potential therapeutic targets for OSA treatment.