The term “athlete’s paradox” describes a condition characterized by high amounts of intramyocellular lipid (IMCL) fat in the muscles observed both in patients with obesity and/or type 2 diabetes mellitus (T2DM), and in endurance-trained athletes. In obese individuals, the IMCL depots are located mainly in fast-twitch muscle fibers and contain high amounts of ceramides and diacylglycerols (DAGs), as well as low concentrations of perilipin 5 (PLIN5) and triacylglycerols (TAGs). In contrast, in endurance-trained athletes, IMCL droplets are situated primarily in slow-twitch muscle fibers and carry high amounts of TAGs and PLIN5 along with low concentrations of lipid metabolites, such as DAGs and ceramides. The intracellular localization of IMCL depots also differs between endurance-trained athletes and patients with obesity. In particular, in athletes, lipid droplets are located predominantly in close relation to mitochondria and the endoplasmic reticulum, while in obese individuals, they may be found in the sarcolemma, subsarcolemmal, or perinuclear regions.
The paradoxical observation that high IMCL content is associated with both insulin resistance and insulin sensitivity has puzzled researchers for decades. Several possible explanations have been proposed to account for this phenomenon, which are summarized below.
- Lipid turnover: One hypothesis is that the rate of lipid turnover, or the balance between lipid uptake and oxidation, determines the metabolic effects of IMCL accumulation. According to this view, athletes have a higher capacity to utilize lipids as fuel during exercise and recovery, which prevents the accumulation of harmful lipid intermediates that impair insulin signaling. Obese individuals, on the other hand, have a lower rate of lipid oxidation and a higher rate of lipid uptake, which leads to the accumulation of DAGs and ceramides that interfere with insulin action.
- Lipid composition: Another hypothesis is that the composition of lipids within the IMCL droplets influences insulin sensitivity. Specifically, it has been suggested that the degree of saturation of DAGs and TAGs modulates their effects on insulin signaling. Saturated DAGs and TAGs are more likely to activate protein kinase C (PKC) isoforms that inhibit insulin receptor substrate 1 (IRS-1) phosphorylation and downstream signaling pathways. Unsaturated DAGs and TAGs are less likely to activate PKC and may even have protective effects on insulin action. Moreover, the ratio of TAGs to DAGs may also affect insulin sensitivity, as TAGs are more inert than DAGs and may buffer the effects of DAGs on PKC activation.
- Lipid localization: A third hypothesis is that the subcellular localization of IMCL droplets determines their impact on insulin sensitivity. It has been proposed that IMCL droplets that are closely associated with mitochondria and the endoplasmic reticulum facilitate lipid oxidation and prevent lipotoxicity. In contrast, IMCL droplets that are located away from these organelles may impair mitochondrial function and induce endoplasmic reticulum stress, which contribute to insulin resistance. Furthermore, the spatial distribution of IMCL droplets within different muscle fiber types may also affect insulin sensitivity, as slow-twitch fibers have a higher oxidative capacity than fast-twitch fibers.
In conclusion, the athlete’s paradox is a complex phenomenon that reflects the interplay between various factors that influence the metabolic consequences of IMCL accumulation in skeletal muscle. Further research is needed to elucidate the molecular mechanisms underlying this paradox and to identify potential therapeutic targets for improving insulin sensitivity in patients with obesity and/or T2DM.
References:
: Li X et al., Skeletal Muscle Lipid Droplets and the Athlete’s Paradox. Cells 2019;8(3):249.
: Coen PM et al., The Athlete’s Paradox: Alterations in Intramuscular Lipid Synthesis and Diacylglycerol Saturation Influence Insulin Action. Diabetes 2016;65(Suppl 1):A28-A29.
: Wolins NE et al., The athlete’s paradOXpat: how lipid droplet size and lipid droplet number affect insulin sensitivity. J Physiol 2018;596(3):365-366.
: Goodpaster BH et al., The athlete’s paradox, insulin resistance and diabetes. British Heart Foundation 2016.
: Goodpaster BH et al., Intramuscular lipid and insulin resistance: a population-based study. Diabetes 2005;54(1):33-39.
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