Dubé JJ, Coen PM, DiStefano G, Chacon AC, Helbling NL, Desimone ME, Stafanovic-Racic M, Hames KC, Despines AA, Toledo FG, Goodpaster BH. Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance. Am J Physiol Endocrinol Metab 307: E1117-E1124, 2014. First published October 28, 2014; doi:10.1152/ajpendo.00257.2014.-We hypothesized that acute lipid-induced insulin resistance would be attenuated in highoxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload. lipids; mitochondria; skeletal muscle CHRONIC SUBSTRATE OVERLOAD, coupled with physical inactivity, is a key mediator of the development of obesity and insulin resistance (49). It has been suggested that mitochondrial dysfunction (1, 17), perhaps a result of nutrient oversupply, particularly saturated fatty acids and/or physical inactivity, plays a key role in decreased insulin action observed in the obese state. However, there is evidence to suggest that mitochondrial content and performance are normal in insulinresistant obese subjects (14). Although there is controversy regarding the influence of mitochondrial performance on the development of insulin resistance (17,22), there is little debate that increased physical activity (i.e., aerobic exercise) provides a necessary stimulus for increased mitochondrial content (24), capacity for fat oxidation (6), and improved insulin sensitivity (13). Yet few studies have directly assessed the effects of lipid oversupply on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance in high-vs. lowoxidative muscle (9, 40).Using the exogenous lipid infusion model of insulin resistance (7, 26), we hypothesized that excess fatty acids would be preferentially oxidized in enduranc...

Purpose The goal of this study was to explore the effect of lifelong aerobic exercise (i.e. chronic training) on skeletal muscle substrate stores (intramyocellular triglyceride [IMTG] and glycogen), skeletal muscle phenotypes, and oxidative capacity (ox), in older endurance-trained master athletes (OA) compared to non-competitive recreational younger (YA) athletes matched by frequency and mode of training. Methods Thirteen OA (64.8±4.9 yo) exercising ≥ 5 times/week were compared to 14 YA (27.8±4.9 yo) males and females. IMTG, glycogen, fiber types, succinate dehydrogenase (SDH) and capillarization were measured by immunohistochemistry in vastus lateralis biopsies. Fat-ox and carbohydrate (CHO)-ox were measured by indirect calorimetry before and after an insulin clamp and during a cycle ergometer graded maximal test. Results V̇O2peak was lower in OA than YA. OA had greater IMTG in all fiber types and lower glycogen stores than YA. This was reflected in greater proportion of type I and less type II fibers in OA. Type I fibers were similar in size, while type II fibers were smaller in OA compared to YA. Both groups had similar SDH content. Numbers of capillaries per fiber were reduced in OA but with a higher number of capillaries per area. Metabolic flexibility and insulin sensitivity were similar in both groups. Exercise metabolic efficiency was higher in OA. At moderate exercise intensities, CHO-ox was lower in OA but with similar Fatox. Conclusion Lifelong exercise is associated with higher IMTG content in all muscle fibers and higher metabolic efficiency during exercise that are not explained by differences in muscle fibers types and other muscle characteristics when comparing older to younger athletes matched by exercise mode and frequency.