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

Abstract

ObjectiveIntramyocellular 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.MethodsWe 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).ResultsWe 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.ConclusionsOur 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.

A 7‐day high‐fat, high‐calorie diet induces fibre‐specific increases in intramuscular triglyceride and perilipin protein expression in human skeletal muscle

“…; Daemen et al . ). Accumulation of IMTG close to the plasma membrane may be detrimental due to the close proximity to key components of the insulin signalling cascade.…”

“…Increased IMTG content near the plasma membrane of muscle fibres has been associated with insulin resistance (Chee et al 2016) particularly if IMTG is stored in larger LDs (Nielsen et al 2017;Daemen et al 2018). Accumulation of IMTG close to the plasma membrane may be detrimental due to the close proximity to key components of the insulin signalling cascade.…”

“…; Daemen et al . ). To detect nuanced changes in IMTG stores following a HFHC diet, we employed our previously validated microscopy techniques (Shepherd et al .…”

“…The primary aim of this study was to test the hypothesis that in healthy individuals that have consumed a HFHC diet for 7 days there is an increase in IMTG stores and a reduction or no change in the concentration of lipid metabolites known to disrupt the insulin signalling cascade in insulin-resistant states. Fibre type and subcellular distribution of IMTG, as well as the size of LDs containing IMTG are all closely linked to insulin resistance (Chee et al 2016;Nielsen et al 2017;Daemen et al 2018). To detect nuanced changes in IMTG stores following a HFHC diet, we employed our previously validated microscopy techniques (Shepherd et al , 2013(Shepherd et al , 2017 to allow us to investigate changes in LD morphology and subcellular distribution on a fibre type-specific basis.…”

When bigger isn't better: understanding the anabolic resistance of obese skeletal muscle

“…Furthermore, mTORC1-lysosome complexes migrate to the periphery of skeletal muscle fibres in response to feeding and exercise, where ribosomal machinery and capillaries containing nutrients are located (Hodson et al 2017). Given the greater subsarcolemmal distribution of intramuscular triglycerides in OB compared to healthy individuals (Daemen et al 2018), it would be intriguing to determine if intramuscular fat depots of OB may physically and/or biochemically interfere with the sarcolemmal targeting of mTORC1 and, thus, its kinase activity. Therefore, while traditional Western blot techniques such as those used by Beals and colleagues (2018) have long been used to estimate mTOR pathway activation, important mechanistic insights that can only be observed looking at Journal Club J Physiol 597.8 cellular localization of signalling molecules may be missed.…”