Altered intramuscular network of lipid droplets and mitochondria in type 2 diabetes

Abstract

Excessive storage of lipid droplets (LDs) in skeletal muscles is a hallmark of type 2 diabetes. However, LD morphology displays a high degree of subcellular heterogeneity and varies between single muscle fibers, which impedes the current understanding of lipid-induced insulin resistance. Using quantitative transmission electron microscopy (TEM), we conducted a comprehensive single-fiber morphological analysis to investigate the intramuscular network of LDs and mitochondria, and the effects of 8 wk of high-intensity interval training (HIIT) targeting major muscle groups, in patients with type 2 diabetes and nondiabetic obese and lean controls. We found that excessive storage of intramuscular lipids in patients with type 2 diabetes was exclusively explained by extremely large LDs situated in distinct muscle fibers with a location-specific deficiency in subsarcolemmal mitochondria. After HIIT, this intramuscular deficiency was improved by a remodeling of LD size and subcellular distribution and mitochondrial content. Analysis of LD morphology further revealed that individual organelles were better described as ellipsoids than spheres. Moreover, physical contact between LD and mitochondrial membranes indicated a dysfunctional interplay between organelles in the diabetic state. Taken together, type 2 diabetes should be recognized as a metabolic disease with high cellular heterogeneity in intramuscular lipid storage, underlining the relevance of single-cell technologies in clinical research. Furthermore, HIIT changed intramuscular LD storage toward nondiabetic characteristics.