A Fresh Look at Fuel Selection in Working Muscle

Metabolic Syndrome and Related DisordersVol. 21, No. 1 EditorialFree AccessA Fresh Look at Fuel Selection in Working MuscleHawley E. Kunz and Ian R. LanzaHawley E. KunzEndocrine Research Unit, Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.Search for more papers by this author and Ian R. LanzaAddress correspondence to: Ian R. Lanza, PhD, Endocrine Research Unit, Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55902, USA E-mail Address: lanza.ian@mayo.eduEndocrine Research Unit, Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.Search for more papers by this authorPublished Online:15 Feb 2023https://doi.org/10.1089/met.2022.0087AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Skeletal muscle is unique in its ability to rapidly increase energetic demand from rest to exercise. Even more impressive is that intracellular adenosine triphosphate (ATP) concentrations are well maintained even in the face of >25-fold increases in ATP demand during some types of vigorous exercise. This remarkable feat of bioenergetic homeostasis is achieved through the coordinated metabolic machinery that generates chemical energy from macronutrients. Skeletal muscle is designed to be nimble in its fuel preference depending on the prevailing conditions. For example, under resting postabsorptive conditions healthy muscle prefers to oxidize lipids for fuel, preserving glycogen for future needs and sparing glucose for other tissues (e.g., brain).However, under postprandial conditions where insulin levels are high, skeletal muscle quickly changes its appetite, switching to carbohydrate as a preferred fuel. In the situation of exercise, skeletal muscle has a menu to choose from that includes glycogen and triglyceride in muscle and glucose and fatty acids in blood. The intensity and duration of exercise dictate how skeletal muscle taps into these fuel sources to support the energetic demands of exercise.Flexibility in substrate preference is critical in sustaining physical activity. This concept of metabolic flexibility has become mainstream after the important limb balance studies that were done in the 1990s1,2 and more recent whole-body gas exchange measurements3–5 that demonstrated that people with obesity or type 2 diabetes lose the ability to respond or adapt appropriately to changing conditions. This phenomenon known as metabolic inflexibility has been implicated in insulin resistance and recognized as a central feature of metabolic derangements of obesity and diabetes.The article by Barakati and colleagues takes aim at this important topic from the standpoint of skeletal muscle fuel selection during exercise. The current gold-standard approach is arteriovenous catheterization, which may not be feasible in many situations. The authors describe a technique whereby whole-body gas exchange data are used to estimate fuel oxidation in working skeletal muscle. The technique goes beyond simply estimating muscle fuel oxidation from indirect calorimetry, which represents fuel oxidation of many tissues in addition to muscle. Instead, the increments in VO2 and VCO2 from rest to exercise are used to calculate a respiratory exchange ratio in working muscle (ΔRER) and estimate the fraction of fuel supplied by lipid.This approach is appealing because it represents an alternative to the invasive limb balance studies and is conceivably more representative of fuel oxidation in working muscle than the conventional use of whole-body indirect calorimetry. There are several noteworthy aspects of this study. First, Barakati et al provide data to support that ΔRER appropriately estimates fuel use in exercising muscle at very low intensities well below the lactate threshold that could be maintained at steady state. Whether this approach has utility at higher intensities that go beyond mild exercise and require energy from both oxidative and nonoxidative processes remains to be determined. The authors go on to evaluate the extent to which insulin sensitivity influences fuel preference of working muscle in young sedentary individuals. Surprisingly, they found that insulin-stimulated glucose disposal did not predict fuel selection during muscle activity, and that carbohydrate was the preferred substrate in the working muscle of very sedentary individuals.Furthermore, muscle citrate synthase activity, a proxy for mitochondrial content, was a significant predictor of fat oxidation during exercise. These findings suggest that metabolic inflexibility in response to exercise may arise from distinct mechanisms to those that drive metabolic inflexibility in response to a meal. The extent to which these findings go beyond the situation of very mild exercise are unclear, particularly given prior literature demonstrating distinct patterns of substrate utilization during moderate exercise in people with and without obesity.4 From this study, it is difficult to ignore the possibility that whole-body indirect calorimetry overestimates muscle lipid oxidation during exercise. Sedentary individuals appear to have greater reliance on carbohydrate as a fuel for skeletal muscle at very low intensities than previously believed.References1. Kelley DE, Mokan M, Simoneau JA, et al. Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest 1993;92:91–98. Crossref, Medline, Google Scholar2. Kelley DE, Simoneau JA. Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. J Clin Invest 1994;94:2349–2356. Crossref, Medline, Google Scholar3. Horowitz JF, Klein S. Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity. J Appl Physiol 2000;89:2276–2282. Crossref, Medline, Google Scholar4. Goodpaster BH, Wolfe RR, Kelley DE. Effects of obesity on substrate utilization during exercise. Obes Res 2002;10:575–584. Crossref, Medline, Google Scholar5. Braun B, Sharoff C, Chipkin SR, et al. Effects of insulin resistance on substrate utilization during exercise in overweight women. J Appl Physiol 2004;97:991–997. Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 21Issue 1Feb 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Hawley E. Kunz and Ian R. Lanza.A Fresh Look at Fuel Selection in Working Muscle.Metabolic Syndrome and Related Disorders.Feb 2023.1-2.http://doi.org/10.1089/met.2022.0087Published in Volume: 21 Issue 1: February 15, 2023Online Ahead of Print:November 1, 2022PDF download