Intramuscular triglyceride synthesis: importance in muscle lipid partitioning in humans

Abstract

Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type 2 diabetes, and have very low risk of diabetes, termed the "athlete's paradox." We now know that IMTG synthesis is positively related to insulin sensitivity, but the exact mechanisms for this are unclear. To understand the relationship between IMTG synthesis and insulin sensitivity, we measured IMTG synthesis in obese control subjects, endurance-trained athletes, and individuals with type 2 diabetes during rest, exercise, and recovery. IMTG synthesis rates were positively related to insulin sensitivity, cytosolic accumulation of DAG, and decreased accumulation of C18:0 ceramide and glucosylceramide. Greater rates of IMTG synthesis in athletes were not explained by alterations in FFA concentration, DGAT1 mRNA expression, or protein content. IMTG synthesis during exercise in Ob and T2D indicate utilization as a fuel despite unchanged content, whereas IMTG concentration decreased during exercise in athletes. mRNA expression for genes involved in lipid desaturation and IMTG synthesis were increased after exercise and recovery. Further, in a subset of individuals, exercise decreased cytosolic and membrane di-saturated DAG content, which may help explain insulin sensitization after acute exercise. These data suggest IMTG synthesis rates may influence insulin sensitivity by altering intracellular lipid localization, and decreasing specific ceramide species that promote insulin resistance.

Magnetic resonance spectroscopy analysis of intramyocellular lipid composition in lipodystrophic patients and athletes

“…We found that the athletes’ IMCL was significantly lower (soleus) or similar (tibialis anterior) to controls. Although this appears to contradict well-known literature reports of an athlete’s paradox using both biopsy methods (13,28,32–34) and 1 H MRS (35,36), this finding is in agreement with literature that reports no such paradox compared to old or young controls (37), obese individuals (38), or in certain fibre types (14). It is known that athletes can have a large depletion-repletion range of IMCL and it is possible that IMCL had not fully recovered since the last training session (24 – 48 hrs prior) as IMCL can still rise significantly after these intervals (39).…”

The Importance of Fatty Acids as Nutrients during Post-Exercise Recovery

“…One study directly measured post-exercise IMTG synthesis by labeled palmitate infusion over 2 h following 90 min of moderate-intensity exercise, and found IMTG fractional synthesis rates to be negative in endurance-trained subjects in the fasted state [10]. This suggests that IMTG is not synthesized in early fasted recovery, but rather can contribute as an energy substrate.…”

“…These processes are energy demanding and accompanied by enhanced post-exercise oxygen consumption (EPOC), of which the magnitude is dependent on exercise duration and intensity [1]. Besides EPOC, the relative contribution from fatty acid (FA) oxidation for whole-body energy turnover is increased, demonstrated by a decreased respiratory exchange ratio (RER), for several hours following aerobic exercise in both untrained and endurance-trained individuals [2][3][4][5][6][7][8][9], and notably also in obese and type 2 diabetic subjects [10]. Even with a carbohydrate-rich meal intake in recovery, the contribution of FAs to oxidation is still increased when compared with resting control conditions [2,4].…”

Skeletal muscle ceramides and relationship with insulin sensitivity after 2 weeks of simulated sedentary behaviour and recovery in healthy older adults

“…Indeed, it has been shown that ceramides contained in the muscle subfraction enriched in the lipid membranes (subsarcolemmal) are more closely associated with insulin sensitivity in humans (Chung et al 2017;Chung et al 2018). This is probably because of the proximity of these lipid intermediates to the cell membranes, thus increasing the probability of causing inhibition of key insulin signalling events (Bergman et al 2012;Bergman et al 2018;Perreault et al 2018). Even more recent work has validated the importance of not only plasma membrane (subsarcolemmal), but also mitochondrial/endoplasmic reticulum, and nuclear enriched subfraction localization of select ceramide and diacylglycerol species, as well as their relationship with insulin sensitivity .…”