Cell Metabolism

Perspective Exercise Metabolism: Historical Perspective John A. Hawley,1,2,* Ronald J. Maughan,3 and Mark Hargreaves4 1Mary

MacKillop Institute for Health Research, Centre for Exercise & Nutrition, Australian Catholic University, VIC 3065, Australia for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, L3 3AF, UK 3School of Sport, Exercise and Health Sciences, Loughborough University, Leicestershire, LE11 3TU, UK 4Department of Physiology, The University of Melbourne, Parkville, Victoria 3010, Australia *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.06.016 2Institute

The past 25 years have witnessed major advances in our knowledge of how exercise activates cellular, molecular, and biochemical pathways with regulatory roles in training response adaptation, and how muscle ‘‘cross-talk’’ with other organs is a mechanism by which physical activity exerts its beneficial effects on ‘‘whole-body’’ health. However, during the late 19th and early 20th centuries, scientific debate in the field of exercise metabolism centered on questions related to the sources of energy for muscular activity, diet-exercise manipulations to alter patterns of fuel utilization, as well as the factors limiting physical work capacity. Posing novel scientific questions and utilizing cutting-edge techniques, the contributions made by the great pioneers of the 19th and early 20th centuries laid the foundation on which much of our present knowledge of exercise metabolism is based and paved the way for future discoveries in the field. Background The application of molecular techniques to exercise metabolism during the past few decades has provided greater understanding of the multiplicity, complexity, and ‘‘cross-talk’’ between the numerous cellular networks involved in divergent exercise responses. The role of nutrient availability in modifying training adaptation and enhancing exercise capacity has also received much scientific enquiry during this time. However, many of the key contributions that laid the groundwork for the molecular synthesis of the last half-century can be traced back to the outcomes from studies conducted in the late 19th and early 20th centuries. During this time, many investigations employing a variety of exercise and diet manipulations were performed in Universities throughout Europe and North America in an attempt to resolve such questions as ‘‘what fuels were utilized by contracting skeletal muscle during exercise’’ and ‘‘what limits exercise capacity?’’ Many of the ‘‘classic’’ studies undertaken in this period were by pioneers in the field who posed novel scientific questions and developed innovative techniques while working in laboratories that were destined to become ‘‘hotbeds’’ of research into muscle metabolism for future generations. This brief historical synopsis describes how several major discoveries of the past century (and beyond) have impacted on our current knowledge of muscle metabolism during exercise. The Early Years Today, it is well accepted that the fuel to support contracting skeletal muscle during continuous exercise of more than a few minutes duration is derived from both intra- and extra-muscular carbohydrate and lipid substrates, with only a minor contribution from amino acids. Furthermore, there is consensus that the primary determinants of the balance of carbohydrate (muscle and liver glycogen and blood glucose from ingested carbohydrate and gluconeogenesis) and lipid (adipose and intramuscular triglycerides as well as blood-borne free fatty acids [FFAs] and triglycerides) fuels for active muscle are the relative exercise intensity (expressed as a percentage of an individual’s maximum 12 Cell Metabolism 22, July 7, 2015 ª2015 Elsevier Inc.

oxygen uptake [VO2max]) (Romijn et al., 1993; van Loon et al., 2001) and the composition of the diet in the preceding days (Bergstro¨m et al., 1967). But this was not always the case! The closing years of the 19th century and the first decades of the 20th were marked by intense debate concerning the relative importance of carbohydrate, fat, and protein as sources of energy for muscular activity. The prevailing view was that carbohydrate was the only fuel that could be used to power muscle contraction and that fat was first transformed into carbohydrate before it could be oxidized as an energy source, with a considerable loss of energy in the process. However, Nathan Zuntz (Zuntz 1896, 1901) and his co-workers (Frentzel and Reach, 1901) were convinced that both fat and carbohydrate could be used as energy sources and showed that manipulation of the proportions of fat and carbohydrate in the diet in the preceding days resulted in corresponding changes in the non-protein respiratory exchange ratio (RER: oxygen uptake [VO2]/carbon dioxide output [VCO2]) during subsequent exercise. They also showed a higher oxygen cost of physical activity (12%) when fat was the principal fuel oxidized. In the succeeding decades, many others contributed to the debate about the fuel sources for muscular activity, but a resolution was only slowly reached. Part of the uncertainty arose from the limitations of the available methodologies, which did not allow for accurate monitoring of external power output during exercise or of reliable measurement of substrate use. Estimations of fat and carbohydrate oxidation relied entirely on measurement of VO2 and VCO2 at the level of the lungs, with methods for the measurement of the composition of expired air being cumbersome and inexact. Urinary nitrogen excretion was used as an index of protein catabolism. August Krogh made several major contributions to the field including the development of a reliable electrically braked cycle ergometer that allowed precise control of power output (Krogh, 1913). He also improved the existing methods for the analysis of oxygen and carbon dioxide, developing a chemical analyzer that permitted determination of the concentrations of these gases in expired air to a precision of

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Figure 1. Our Understanding of Exercise Metabolism Was Greatly Advanced by Several Methodological Breakthroughs August Krogh and the apparatus he developed for the accurate measurement of gas concentrations in expired air.

0.001% (Krogh, 1920). It is worth noting that the accuracy of these methods far exceeds that of the electronic analyzers used in most modern-day exercise physiology laboratories (Figure 1). Using these new methods, Krogh and Lindhard (1920) performed an extensive series of studies (albeit on a small number of experimental subjects) on the effects of diet composition on muscle substrate use. They essentially confirmed the results of Zuntz and co-workers (Frentzel and Reach, 1901; Zuntz 1896, 1901) showing that the proportions of fat and carbohydrate oxidized during steady-state exercise varied with the composition of the preceding diet and that the oxygen cost of exercise was about 11% lower when using carbohydrate rather than fat. These workers believed that the contribution of protein to oxidative metabolism was small, but on the basis of an increased urinary excretion of nitrogen, Cathcart (1925) proposed that the contribution of protein to overall metabolism increased during ‘‘very prolonged’’ or intense exercise. Even as late as 1924, A.V. Hill was of the opinion that conversion of fat to carbohydrate before oxidation might still be necessary and cited the higher oxygen cost of fat-based fuels as support for this argument (Hill, 1924). These findings continued to be disputed, with Reynolds et al. (1927) reporting no difference in mechanical efficiency during exercise after different diets were fed to subjects. During his illustrious career, Krogh made several trips abroad and established links with, among others, the Harvard Fatigue Laboratory in Boston. The first and only scientific director of the Harvard Fatigue laboratory was Dr. David Bruce Dill, who was an influential driving force behind the laboratory’s numerous scientific accomplishments. Dill’s group undertook studies of their own on exercise metabolism and the limits to work capacity (Dill et al., 1932), while also fostering lasting collaborations with many scientists throughout the world. In 1922, Hill received the Nobel Prize for Physiology or Medicine for his work on heat production in contracting muscle and was anxious to reconcile the physical processes occurring during muscle contraction with the prevailing metabolic activity. The English school of biochemists, led by Fletcher and Hopkins, had already established the importance of the formation of lactic acid during contraction of amphibian muscles under anaerobic conditions and the concomitant suppression of lactate formation in the presence of oxygen (Fletcher, 1907). Subsequently, muscle glycogen was confirmed as the source of the lactate. Otto

Meyerhof shared the 1922 Nobel Prize with Hill for his discovery that the lactate produced during intense exercise can be reconverted to glycogen or further metabolized to CO2 and H2O during recovery after exercise. Hill also articulated the debate, which continues to this day, as to whether maximal exercise is limited by oxygen delivery to the working muscles or by metabolic events occurring within the muscle. In 1923, Hill and Meyerhof proposed that energy needs of contracting muscle could be met by anaerobic or aerobic metabolic pathways (Hill and Meyerhof, 1923). Embden and others later filled in the missing pieces of the metabolic pathways involved in carbohydrate metabolism, but much of this work was disrupted and delayed by the tensions in Europe at this time. In the late 1920s a high-energy phosphate compound (‘‘phosphagen’’) was also found in muscle and was identified as creatine phosphate (Eggleton and Eggleton 1927; Fiske and Subbarow 1927). Creatine phosphate was proposed to be the immediate energy source for active muscle but later studies showed that phosphagen was not a single entity. Indeed, it was not until 1962 that Cain and Davies (1962) finally proved the immediate energy source to be adenosine triphosphate (ATP). Back in Copenhagen, Erik Hohwu¨ Christensen completed his doctoral studies with Krogh and Lindhard on the physiological responses to heavy exercise. Together with Erling Asmussen and Marius Nielsen, Christensen contributed to an intensely productive period of research into muscle metabolism. With Ole Hansen, he undertook a series of studies demonstrating the importance of carbohydrate availability for exercise performance and the influence of the prevailing exercise intensity and duration on muscle metabolism. As is the case today, some early investigators were interested in exercise performance while others viewed exercise merely as another tool that could be used to study physiology and metabolism. The work of Christensen and Hansen (1939a, 1939b) showing that manipulation of the carbohydrate content of the preceding diet resulted in changes in the time for which work at a fixed power output could be sustained was highly predictable from the earlier work of Krogh and Lindhard (1920) who had reported that subjects perceived a fixed, submaximal exercise task to be easier after several days consuming a high carbohydrate diet than when the preceding diet was low in carbohydrate and high in fat. Nevertheless, the studies of Christensen and Hansen (1939a, 1939b) are now widely recognized as landmark discoveries, perhaps because of their practical implications. In the early 1940s, Christensen moved to Stockholm and was a mentor to Drs. Per-Olof A˚strand and Bengt Saltin, who themselves became pioneers in the fields of exercise and muscle physiology. The ‘‘Classic’’ Period of Exercise Biochemistry: 1960–1985 The 25 years that began in the 1960s and progressed through the mid-1980s have been called the ‘‘classic period’’ of exercise biochemistry (Brooks and Mercier 1994) and included major advances in our understanding of how exercise promotes the biosynthesis of mitochondrial proteins in skeletal muscle, the impact of exercise training and diet manipulations on muscle substrate stores and endurance capacity, the fate of lactate during exercise and recovery, and the regulation of muscle protein Cell Metabolism 22, July 7, 2015 ª2015 Elsevier Inc. 13

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Figure 2. Pioneers in the Field of Exercise Metabolism Drs. Jonas Bergstro¨m and Eric Hultman introduced the percutaneous needle biopsy technique to studies of human muscle metabolism and were the sole subjects in their landmark paper published in 1966, investigating the interactive effects of exercise and diet on muscle glycogen resynthesis.

balance. The results of many of the investigations that provided new insight into muscle regulatory mechanisms relied on new approaches to old questions and/or the application of established techniques already employed in other disciplines to the field of muscle metabolism. At the start of the 1960s, little was known regarding the factors regulating the biogenesis of mitochondria in skeletal muscle. The seminal work of Dr. John Holloszy (Holloszy, 1967) heralded a major advance in unravelling the cellular events controlling muscle bioenergetics when he discovered that the muscles of trained rats exhibited higher levels of mitochondrial proteins than those of untrained animals. Utilizing a strenuous treadmill protocol consisting of both prolonged, continuous, and sprint interval running, Holloszy (1967) showed that the mitochondria from muscles of exercised animals exhibited a high level of respiratory control and tightly coupled oxidative phosphorylation. The increase in electron transport capacity was associated with a concomitant rise in the capacity to produce ATP, and Holloszy (1967) concluded that this adaptation ‘‘may partially account for the increase in aerobic work capacity that occurs with regularly performed, prolonged exercise.’’ Using the percutaneous needle biopsy technique to excise small (100–200 mg) samples of muscle, it became relatively easy to conduct invasive studies of muscle metabolism and determine the impact of training, diet, and other manipulations on selected biochemical (Holloszy and Booth 1976), metabolic (Saltin 1973), histological (Gollnick et al., 1972), and contractile (Saltin et al., 1977) characteristics. Around this time, Goldstein (1961) proposed that a ‘‘humoral factor’’ was liberated by muscle during contraction that ‘‘activates the glucose transport system’’ and helps ‘‘regulate carbohydrate metabolism.’’ In an attempt to clarify whether a systemic ‘‘humoral’’ factor or a local factor in muscle cells could explain the rapid post-exercise resynthesis of muscle glycogen, two Swedish scientists, Drs. Jonas Bergstro¨m and Eric Hultman (Figure 2), undertook an ingenious study involving several days of exercise-diet manipulation in which (in keeping with the Scandinavian tradition) they themselves acted as the sole subjects (Bergstro¨m and Hultman, 1966). On the first day of their experiment, the two investigators sat on either side of a bicycle ergometer and each cycled with one leg, while the other leg rested. Exercise was continued until they were exhausted, at which point they performed biopsies on each other from both 14 Cell Metabolism 22, July 7, 2015 ª2015 Elsevier Inc.

legs. During the rest of the day and for the next 2 days, Bergstro¨m and Hultman consumed a high carbohydrate diet and took further biopsies, again from both legs, on the morning of the second and third day. Muscle glycogen content in the exercised leg was very low immediately after exhaustive cycling, while the non-exercised leg had still normal glycogen stores. After 1 day of the high-carbohydrate diet, the glycogen content of the exercised leg had risen from almost zero to higher values than the resting leg and continued to increase during the subsequent 2 days of the diet, such that the values were 2-fold higher than the non-exercised leg on day 3 (Figure 3). Bergstro¨m and Hultman (1966) concluded that exercise-induced glycogen depletion enhanced the resythesis of glycogen and this ‘‘persistent enhancing effect’’ was ‘‘localized to the muscle cells’’ by unknown factors. With remarkable insight, they also speculated ‘‘some of the beneficial effects of exercise in normal as well as diabetic subjects could be mediated by this factor’’ (Bergstro¨m and Hultman, 1966). The results of this study laid the foundations for future work into the regulation of muscle substrate metabolism during exercise undertaken by Scandinavian scientists (including Drs. Bengt Saltin and Lars Hermansen) and their collaborators (including Drs. Phillip Gollnick and David Costill from the USA) in the subsequent two decades. Also at this time, the results of studies using labeled glucose and FAs along with direct measurements of glucose and FA uptake across exercising limbs (Hagenfeldt and Wahren, 1966; Havel et al., 1967; Wahren et al., 1971) demonstrated that contracting skeletal muscle could utilize these blood-borne fuels during exercise. The role of substrate availability in determining the interactions between fat and carbohydrate utilization during exercise, as well as nutritional manipulation to improve exercise capacity, was also examined (Pernow and Saltin, 1971). Dr. George Brooks examined various aspects of lactate metabolism during exercise and identified lactate as an important metabolic intermediate during exercise in a reprise of the Cori cycle (Brooks, 1986). Henrik Galbo, working at the Panum Institute in Copenhagen, studied the influence of substrate availability on the hormonal response to prolonged exercise (Galbo et al., 1979), while also completing numerous investigations of the endocrine responses and adaptations to exercise training. It had been recognized since the early 1900s that exercise could enhance insulin action (Lawrence, 1926) and studies in the 1970s and 1980s verified the importance of ‘‘local factors’’ within contracting skeletal muscle in mediating this effect (Richter et al., 1989; Wallberg-Henriksson and Holloszy 1984). It was also shown that skeletal muscle could release biologically active molecules, so called ‘‘myokines’’ (Pedersen et al., 2003) and that this ‘‘cross-talk’’ with other organs (including adipose tissue, liver, pancreas, bone, and the brain) was one mechanism to explain how exercise mediated many of its beneficial systemic ‘‘wholebody’’ effects. The use of labeled tracers as metabolic probes of whole-body and limb metabolism contributed to major advances in our understanding of substrate kinetics during exercise and subsequent recovery. Early studies in the 1960s examined glucose (Reichard et al., 1961; Sanders et al., 1964) and FA (Havel et al., 1963, 1967) fluxes using radiolabeled isotopes of glucose and palmitate and demonstrated that exercise increased the turnover of both energy substrates. Later, the application

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Figure 3. The Interactive Effects of Prior Exercise and a Carbohydrate-Rich Diet on the Resynthesis of Muscle Glycogen Muscle glycogen content in resting (dashed line) and exercised (bold line) legs. Biopsies were taken from both legs of the two subjects at the same time on each occasion. Redrawn from Bergstro¨m and Hultman (1966). Muscle glycogen synthesis after exercise: an enhancing factor localized to the muscle cells in man. Reprinted with permission from Nature Publishing Group.

of stable isotopes, either alone or in conjunction with radiolabeled isotopes, allowed for the investigation of carbohydrate, fat, and protein metabolism during and after exercise (Chesley et al., 1992; Rennie et al., 1981; Romijn et al., 1993; van Loon et al., 2001), the effects of training interventions on substrate fluxes (Coggan et al., 1995; Friedlander et al., 1997, 1998), and investigation of the influence of nutritional interventions on exercise metabolism (Bosch et al., 1993) and post-exercise substrate balance. The interactive effects of exercise and orally administered carbohydrate/amino acids on muscle glucose kinetics, post-exercise muscle glycogen synthesis and the protein synthetic response received much attention and laid the foundation on which our current understanding of muscle metabolism in response to exercise and nutritional intake is based (Figure 3). The Dawn of the Molecular Age The elucidation of the chemical structure of DNA, along with remarkable advances in molecular biology and related analytical techniques over the last 50 years, catalyzed an increased understanding of the cellular and molecular mechanisms that regulate muscle metabolism during exercise and the adaptive responses to exercise training. The molecular bases of skeletal muscle adaptations to exercise (i.e., increased mitochondrial mass, altered substrate metabolism, enhanced angiogenesis, or myofiber hypertrophy) fundamentally involve increased expression and/or

activity of key proteins, mediated by an array of signaling events, pre- and post-transcriptional processes, regulation of translation and protein expression, and modulation of protein (enzyme) activities and/or intracellular localization. There are multiple stimuli associated with endurance- and resistance-based exercise, various signaling kinases that respond to these divergent stimuli, and numerous downstream pathways and targets of these kinases (Egan and Zierath 2013; Coffey and Hawley 2007). There are complex spatial and temporal interactions between these various elements that combine to produce the integrated response to an exercise challenge and ultimately result in functional improvements and alterations in phenotype (Hawley et al., 2014). An important concept developed during the past decade is that the responses to exercise training reflect the cumulative effects of the responses to repeated, single exercise bouts (Perry et al., 2010). Acute and transient changes in gene transcription following a single exercise bout, when reinforced by repeated exercise stimuli, result in chronic effects on protein expression that form the basis of skeletal muscle training adaptation and improvements in exercise capacity/performance (Hawley 2002). Similarly, removal of the regular exercise stimulus during a period of ‘‘detraining’’ results in the rapid reversal of the training adaptation (Coyle et al., 1984). Increases in skeletal muscle oxidative capacity and the associated alteration in substrate metabolism are hallmarks of endurance exercise adaptation, with the regulation of mitochondrial biogenesis involving the interplay between the nuclear and mitochondrial genomes, synthesis of lipids and proteins, and the stoichiometric assembly of multi-subunit protein complexes into a functional respiratory chain (Hood et al., 2006). One of the first studies to probe the molecular basis of this adaptation was that of Williams and colleagues (1986), who observed increased cytochrome c mRNA and mitochondrial DNA following chronic electrical stimulation of rabbit tibialis anterior muscle. Regulation at the transcriptional level was confirmed when it was observed that a single bout of exercise transiently increased GLUT4 and citrate synthase gene transcription in rat skeletal muscle (Neufer and Dohm, 1993). Subsequently several independent groups observed transient increases in mRNA levels of selected metabolic genes, transcription factors, and coactivators in human skeletal muscle following a single bout of exercise (Kraniou et al., 2000; Pilegaard et al., 2000, 2003; Russell et al., 2005). In the 1990s, the AMP-activated protein kinase (AMPK) was shown to be activated during exercise and was implicated in the regulation of FA oxidation (Winder and Hardie, 1996). Subsequent work demonstrated that the AMPK mediates many of the acute responses to exercise in response to changes in cellular energy status by inhibiting ATP-consuming pathways, and activating pathways involved in carbohydrate and FA metabolism to restore muscle [ATP]. While the AMPK functions to orchestrate many of the acute responses to exercise, this kinase also has important roles in the adaptive response of skeletal muscles to endurance exercise training because of its ability to alter muscle fuel reserves and the expression of several exercise-responsive genes (Frøsig et al., 2004; McGee and Hargreaves, 2010). An important development in unraveling the cellular events that promote mitochondrial biogenesis was the discovery of the transcriptional coactivator peroxisome proliferator-activated gamma coactivator 1 (PGC-1a) from the Speigelman lab (Wu Cell Metabolism 22, July 7, 2015 ª2015 Elsevier Inc. 15

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Perspective et al., 1999). Because the PGC-1 coactivators are highly versatile and interact with many different transcription factors to activate distinct biological programs in different tissues, they have attracted considerable attention for their potential roles in mediating exercise-induced alterations in skeletal muscle mitochondrial biogenesis and angiogenesis (Lin et al., 2005; Yan et al., 2011). That said, it is important to recognize the redundancy and compensatory mechanisms that exist in the regulation of muscle metabolism (McGee et al., 2014; Yan et al., 2011), implying that multiple mechanisms underpin the adaptive responses to acute and chronic exercise. Exercise effects on gene transcription and the transcriptome are generally not thought to involve fundamental changes in the gene sequence; rather, they arise through epigenetic modifications of DNA and related chromosomal proteins (Rasmussen et al., 2014). Such epigenetic modifications link changes in the environment, notably exercise or activity level, with alterations in gene expression and function. The two major epigenetic modifications are DNA methylation and post-translational histone modifications, including acetylation, methylation, phosphorylation, and ubiquitination. The modulation of gene transcription and translation by non-coding RNAs, including micro RNAs, is another form of epigenetic modification. Increasingly, genomewide association studies identify potential ‘‘exercise and performance genes’’ and this provides biological insights into many aspects of the exercise response-adaptation process, including the biological bases of individual responses to such intervention. These remarkable advances in molecular and cell biology and analytical technologies have resulted in a greater understanding of the molecular bases of skeletal muscle adaptations to acute and chronic exercise. In a companion paper, Zierath and Wallberg-Henriksson (2015) offer insights into the future of exercise biology. However, as we move forward we should not forget the pioneering studies by some of the great scientists of the 19th and 20th centuries that underpin our current knowledge of exercise metabolism. ACKNOWLEDGMENTS J.A.H. is supported by grants from the Novo Nordisk Foundation and a Collaborative Research Network Grant from The Australian Catholic University.

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Cell Metabolism 22, July 7, 2015 ª2015 Elsevier Inc. 17

Exercise Metabolism: Historical Perspective.

The past 25 years have witnessed major advances in our knowledge of how exercise activates cellular, molecular, and biochemical pathways with regulato...
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