Distinct lipid droplet characteristics and distribution unmask the apparent contradiction of the athlete's paradox

Sabine Daemen, Anne Gemmink, Bram Brouwers, Ruth C.R. Meex, Peter R. Huntjens, Gert Schaart, Esther Moonen-Kornips, Johanna Jörgensen, Joris Hoeks, Patrick Schrauwen, Matthijs K.C. Hesselink

Individuals with type 2 diabetes present with increased storage of intramyocellular lipid (IMCL). Paradoxically, IMCL levels are also elevated in endurance trained athletes, who are very insulin sensitive. This phenomenon is known as the athlete’s paradox. Daemen, Gemmink, et al. examined the athlete’s paradox in individuals with similar levels of IMCL but over a wide range of insulin sensitivity. They found that insulin sensitive, trained individuals possess high levels of muscle fat that is dispersed in small lipid droplets in oxidative type I muscle fibers. On the other hand, in the insulin resistant type 2 diabetic state, most of the muscle fat is found in large lipid droplets in the subsarcolemmal space of type II muscle fibers. Therefore, the athlete’s paradox can be explained from a physiological perspective

Objective: Intramyocellular lipid (IMCL) storage negatively associates with insulin resistance, albeit not in endurance-trained athletes. We investigated the putative contribution of lipid droplet (LD) morphology and subcellular localization to the so-called athlete's paradox.

Methods: We performed quantitative immunofluorescent confocal imaging of muscle biopsy sections from endurance Trained, Lean sedentary, Obese, and Type 2 diabetes (T2DM) participants (n = 8/group). T2DM patients and Trained individuals were matched for IMCL content. Furthermore we performed this analysis in biopsies of T2DM patients before and after a 12-week exercise program (n = 8).

Results: We found marked differences in lipid storage morphology between trained subjects and T2DM: the latter group mainly store lipid in larger LDs in the subsarcolemmal (SS) region of type II fibers, whereas Trained store lipid in a higher number of LDs in the intramyofibrillar (IMF) region of type I fibers. In addition, a twelve-week combined endurance and strength exercise program resulted in a LD phenotype shift in T2DM patients partly towards an ‘athlete-like’ phenotype, accompanied by improved insulin sensitivity. Proteins involved in LD turnover were also more abundant in Trained than in T2DM and partly changed in an ‘athlete-like’ fashion in T2DM patients upon exercise training.

Conclusions: Our findings provide a physiological explanation for the athlete's paradox and reveal LD morphology and distribution as a major determinant of skeletal muscle insulin sensitivity.