Abstract
Muscle glycogen is the main substrate during high-intensity exercise and large reductions can occur after relatively short durations. Moreover, muscle glycogen is stored heterogeneously and similarly displays a heterogeneous and fiber-type specific depletion pattern with utilization in both fast- and slow-twitch fibers during high-intensity exercise, with a higher degradation rate in the former. Thus, depletion of individual fast- and slow-twitch fibers has been demonstrated despite muscle glycogen at the whole-muscle level only being moderately lowered. In addition, muscle glycogen is stored in specific subcellular compartments, which have been demonstrated to be important for muscle function and should be considered as well as global muscle glycogen availability. In the present review, we discuss the importance of glycogen metabolism for single and intermittent bouts of high-intensity exercise and outline possible underlying mechanisms for a relationship between muscle glycogen and fatigue during these types of exercise. Traditionally this relationship has been attributed to a decreased ATP resynthesis rate due to inadequate substrate availability at the whole-muscle level, but emerging evidence points to a direct coupling between muscle glycogen and steps in the excitation–contraction coupling including altered muscle excitability and calcium kinetics.
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Avoid common mistakes on your manuscript.
Muscle glycogen metabolism is notably elevated during high-intensity exercise leading to substantial declines after short duration. |
In addition to declines at the whole-muscle level, heterogeneity in cellular and subcellular depletion should be considered and may be a key aspect in a link between muscle glycogen and performance. |
Altered muscle glycogen content results in impaired single and repeated high-intensity exercise tolerance, only if glycogen is reduced below a certain critical level and no consistent effects of muscle glycogen supercompensation are apparent. |
The mechanisms for a coupling between muscle glycogen and performance may be mediated through key steps in the excitation–contraction coupling such as impaired muscle excitability and calcium regulation. |
1 Introduction
Since early studies by Christensen and Hansen [1] demonstrated new insights into the role of fat and carbohydrate metabolism during exercise, a strong relationship between muscle glycogen and performance during prolonged exercise has been well established [2,3,4,5,6,7]. In contrast, the effect of glycogen content on high-intensity (defined here as ≥ 100% VO2max) exercise performance is more ambiguous. During high-intensity exercise, glycogenolysis is the main source for adenosine triphosphate (ATP) resynthesis coupled with creatine phosphate (PCr) breakdown, especially during brief bursts of high-intensity exercise and with an expanded contribution from oxidative phosphorylation as exercise duration increases or when bouts are repeated [8,9,10,11]. This results in substantial PCr depletion and marked perturbations in the intracellular environment including H+ accumulation, increased formation of byproducts of ATP hydrolysis, altered ion homeostasis, increased levels of reactive oxidative species etc. which may all contribute significantly to fatigue development [12,13,14,15]. The relative importance and interactions between these fatiguing mechanisms are still under debate and have been covered in other papers [14,15,16,17,18]. The focus of the present review is to address the role of muscle glycogen metabolism in performance during high-intensity exercise, for example when high-intensity bouts are performed towards the end of a team sport match rather than in a non-fatigued state. In this regard, it is known that ~ 50% of the ATP turnover is fueled by glycogenolysis during a 6-s sprint [11], resulting in a notably high muscle glycogen metabolism. Accordingly, after high-intensity team sport exercise, such as ice hockey, muscle glycogen is reduced by more than 50% concomitant with symptoms of fatigue [19]. Furthermore, at this point, a large proportion of individual fast- and slow-twitch fibers are depleted of glycogen [19], which indicates that fiber-specific utilization of muscle glycogen and possibly the spatial distribution in different subcellular compartments may be key components in a potential link between fatigue development and muscle glycogen depletion [20, 21]. Accordingly, muscle glycogen localized in specific areas within muscle fibers have been suggested to retain distinct regulatory roles and depletion patterns [21,22,23,24,25,26]. This may be particularly important during high-intensity exercise where fatigue development typically manifests in advance of severe muscle glycogen depletion at the whole-muscle level and may be a central factor in previous observations of impaired muscle function instigated by only partially lowered muscle glycogen levels [27,28,29]. Nonetheless, results examining the impact of glycogen content on high-intensity exercise performance are divergent. For example, Hargreaves et al. [30] failed to establish any relationship between glycogen levels and ~ 75 s all-out cycling, whereas Balsom et al. [31] demonstrated that lowered initial glycogen content attenuated exercise tolerance when 6-s sprints interspersed by 30-s recovery intervals were repeated fifteen times.
Moreover, mechanisms linking muscle glycogen content to exercise tolerance are not fully elucidated. Historically, the detrimental effect of lowered muscle glycogen has been attributed to energy deficiency in terms of inadequate glycogen available for breakdown and ATP regeneration at the required rate for maintenance of muscle function at the whole-muscle level [14, 32]. However, this concept has been challenged, and evolving evidence points to a direct link between muscle glycogen content and steps in the excitation–contraction (E–C) coupling including factors related to muscle calcium (Ca2+) regulation and membrane excitability [22, 33,34,35,36]. Thus, effects of lowered muscle glycogen have been observed even after recovery periods where muscle ATP concentration would be normal and under experimental circumstances in vitro where global ATP and PCr levels can be maintained at near resting levels suggesting either a non-metabolic role of muscle glycogen or a localization–specific metabolic decline [27, 28, 34, 37,38,39].
Therefore, the objective of the present review is to examine the evidence linking muscle glycogen content and utilization to performance during high-intensity exercise and delineate possible underlying mechanisms.
2 Muscle Glycogen Storage and Utilization Patterns During High-Intensity Exercise
Glycogen is a readily mobilized storage form of carbohydrates in most cells with the majority stored in skeletal muscle (~ 400 g) and a smaller amount located in hepatocytes (~ 100 g) [40, 41]. Resting levels are 400–600 mmol·kg−1 dw depending on training status and with super compensated levels as high as 450–850 mmol·kg−1 dw [42]. On the other hand values of 200–300 mmol·kg−1 dw have been measured under low carbohydrate dietary conditions [42]. During exercise, these levels can be markedly reduced, but some glycogen (~ 10%) always remains in the muscle even following severe exercise [41]. Metabolism of muscle glycogen accelerates with exercise intensity and above ~ 75% VO2max, carbohydrate is the main substrate, due to a higher power of aerobic ATP generation by carbohydrate combustion [12, 43, 44]. At intensities near and above ~ 100% VO2max the anaerobic turnover of muscle glycogen increases substantially, resulting in a high ATP turnover, but at a high cost in terms of energy efficiency (~ 10 times less ATP per glucose molecule) and resulting in changes in the intracellular milieu [9, 12, 45, 46]. Hence, during a 6-s sprint with a peak intensity of ~ 300% VO2max, approximately 50% of the ATP production is provided by a rapid increase in anaerobic glycolysis accompanied by PCr hydrolysis and only a minor part covered by oxidative phosphorylation (< 10%) (see Fig. 1) [9, 11]. Likewise, during a 30-s all-out exercise scenario ~ 65 to 75% of the energy provision is fueled by anaerobic glycolysis [46, 47] resulting in a notably high muscle glycogen turnover. Thus, ~ 15% reductions have been demonstrated following single 6-s sprints and ~ 20 to 30% reductions after 30-s all-out exercise [9, 11, 46, 48]. Accordingly, high initial glycogenolytic rates of ~ 4.5 mmol glucosyl units·kg−1 dw·s−1 have been estimated and even higher glycogen breakdown rates of up to ~ 7 mmol glucosyl units·kg−1 dw·s−1 transiently during very intense exercise (resulting in glucose 6-phosphate accumulation) (see Fig. 2) [9, 11, 49]. However, already during 30-s maximal exercise, the rate of glycogenolysis/glycolysis is considerably lowered after the initial ~ 15-s concomitant with impaired power output and increased contribution from aerobic energy turnover [9, 11, 46]. Thus, with repeated bouts of high-intensity exercise, the rate of carbohydrate utilization is reduced even at the onset of exercise [46]. This has been proposed to relate to muscle acidosis, the increased reliance on aerobic energy metabolism, and/or a result of the decrease in work capacity and therefore energy requirements caused by fatigue development [9, 11, 49, 50]. Nonetheless, the turnover of muscle glycogen is elevated during high-intensity exercise leading to pronounced declines after short-duration exercise.
ATP turnover rates and muscle metabolism during a first (a) and third (b) bout of high-intensity isokinetic cycling separated by 4-min of rest. Adapted with permission from Parolin et al. [11]
Examples of muscle glycogen breakdown rates during single bouts of exercise at intensities ranging from 75 to approximately 300% VO2max
3 Muscle Glycogen Utilization in Individual Fibers
Muscle glycogen is stored heterogeneously and likewise displays a heterogeneous and fiber-type specific depletion pattern depending on exercise mode, duration, and intensity [20, 25, 29, 32, 51,52,53,54,55]. Thus, during high-intensity exercise essentially all fibers are activated [56] resulting in simultaneous depletion of both slow and fast-twitch fibers with a higher breakdown rate in fast-twitch fibers [12, 19, 20, 48, 55]. For example, declines of 126 and 77 mmol glucosyl units·kg−1 dw in fast- and slow-twitch muscle, respectively, have been reported after 30-s sprinting [48]. However, while a significant amount of glycogen may remain in some individual fibers at cessation of exhaustive high-intensity exercise, a substantial number of fibers can be depleted, even if glycogen at the whole-muscle level remains only partially lowered. For instance, after intermittent team sport exercises such as soccer [57] and ice hockey [19], which are characterized by frequent bouts of high-intensity exercise, more than 50% of slow and fast-twitch fibers in the knee-extensor muscles were depleted or nearly depleted of glycogen (see Fig. 3). Moreover, Gollnick et al. [20] demonstrated that ~ 40% of fast-twitch fibers were low in glycogen after only six 1-min high-intensity exercise bouts. This depletion pattern of individual fibers is comparable to findings obtained following prolonged exercise where large numbers of individual fibers of both fiber-types are depleted of glycogen [7, 29, 52, 53, 55, 58, 59]. On that note, fiber-type differences in glycogen utilization have been linked to distinct molecular signaling responses and could be important for exercise type-specific adaptations such as in insulin sensitivity and mitochondrial morphology in fast and slow-twitch fibers [60]. Moreover, depletion of individual muscle fibers may locally attenuate the ability of these specific fibers to maintain adequate energy production and/or impair E-C coupling processes and subsequent force production to support high-intensity performance as will be discussed in detail in coming sections. Accordingly, higher post-exercise inosine monophosphate (IMP) concentrations have been observed in glycogen-depleted fibers, suggestive of metabolic alterations due to local substrate depletion [61]. In support, large heterogeneity in single fiber PCr and ATP concentrations has been found after exercise pointing to the importance of local energy metabolism in addition to considerations of energy availability at the whole-muscle level [56, 62, 63]. This heterogeneity may indeed be a major component of a potential link between muscle glycogen content and performance during high-intensity exercise in advance of whole-muscle glycogen depletion.
Relative muscle glycogen utilization of individual fibers before and after high-intensity exercise (ice hockey). Adapted with permission from Vigh-Larsen et al. [19]
4 Muscle Glycogen Storage in Distinct Spatial Compartments
In addition to fiber-specific storage and depletion patterns, glycogen is deposited in specific compartments within muscle fibers, possibly exerting specialized regulatory and metabolic functions [21, 23, 24, 26, 64,65,66]. By two-dimensional electron microscopy images (see Fig. 4), three subcellular locations have been defined; (a) intermyofibrillar glycogen located between myofibrils in close contact with the longitudinal part of the sarcoplasmic reticulum (SR) and mitochondria, (b) intramyofibrillar glycogen located between the contractile filaments close to triadic junctions within the transverse tubular system (T-system) and (c) subsarcolemmal glycogen stored below the cell surface membrane (for reviews see Nielsen et al. [21] and Ørtenblad et al. [64]). Specifically, intramyofibrillar glycogen has repeatedly been demonstrated both in rodents and humans to be closely associated with exercise tolerance and muscle function [28, 39, 67, 68]. Most recently, Jensen et al. [68] demonstrated an association between this particular pool and endurance capacity in moderately trained subjects, which has also been demonstrated in highly trained skiers [28]. Also, more pronounced relative utilization of intramyofibrillar glycogen has been demonstrated after high-intensity [69] as well as prolonged exercise [70, 71]. Moreover, near-depleted levels of specifically intramyofibrillar glycogen have been observed after resistance exercise in fast-twitch fibers [72]. This may be facilitated by restricted diffusion capacity in the narrow triadic junctions, formed by the terminal cisternae of the SR, which lies along the T-system, clearly separated from mitochondria and intermyofibrillar glycogen, but with a high local energy turnover during repetitive contractions. Hence, the compartmentalized muscle cell with a high and fluctuating energy metabolism may necessitate rapidly available local energy provision, whereas utilization of distinct subcellular glycogen pools presumably reflects the activation of different ATPases dependent on contractile/exercise task [21]. However, little is known about the precise role of the glycogen pools in providing energy for specific ATPases and/or regulation of E-C coupling, though this can be speculated upon. Thus, intramyofibrillar glycogen located in the adjacent proximity to triadic junctions may be essential for energy supply for maintenance of muscle function in these specific areas. Moreover, both myofibrillar fractions (intra and intermyofibrillar glycogen) likely drive myosin-action crossbridge cycling [24], while intermyofibrillar glycogen additionally has been associated with SR Ca2+ uptake [39]. On the other hand, the subcarcolemmal fractions are supposedly involved in energy provision for Na+-K+-ATPases along the sarcolemma [25]. This localized compartmentalization of energy turnover is in line with findings reporting impaired muscle function in conditions of enzymatical removal of muscle glycogen or inhibition of glycogen phosphorylase, despite maintained globally cellular ATP and PCr concentrations [34, 35, 73, 74]. Together, the existence of different subcellular glycogen pools with distinct utilization, suggests that a link between muscle glycogen content and muscle function may be related to direct effects of localization-specific glycogen on muscle E–C coupling and contractile function.
Representative image of the spatial distribution of muscle glycogen from electron microscopy in musculus triceps brachii before (left) and after (right) ~ 4 min of high-intensity skiing. Black dots = glycogen particles; SS = subsarcolemmal; Intra = intramyofibrillar, IMF = intermyofibrillar. Adapted with permission from Gejl et al. [69]
5 Muscle Glycogen Content and High-Intensity Exercise Performance
The relationship between muscle glycogen content and high-intensity exercise performance has been investigated in numerous studies originally in the 1980s [75,76,77,78,79,80,81,82,83,84] and 1990s [29,30,31, 85,86,87,88,89,90,91,92], while only a few additional studies since then have provided additional insight [93,94,95,96,97,98,99]. The performance measures in these studies can be subdivided into (I) continuous high-intensity exercise (> 60 s duration), (II) single or repeated sprints (< 60 s duration) and (III) neuromuscular contractile performance (voluntary or electrically induced maximal or near-maximal contractions). Results of these studies are summarized in Tables 1, 2 and 3. It should be noted, however, that a major limitation in several of these studies is the lack of muscle glycogen measurements. Instead, classical exercise and dietary strategies have been commonly utilized and successful glycogen manipulations assumed on the basis of previous work. Therefore, the ability to draw conclusions on the relationship between muscle glycogen levels and performance is confounded by indirect assumptions of glycogen depletion based only on exercise and dietary manipulations.
5.1 Continuous High-Intensity Exercise
For continuous high-intensity exercise, we identified three studies measuring muscle glycogen concentrations [29, 30, 86]. In one study, applying the one-legged knee-extensor model, no initial relationship was determined between high-intensity exercise lasting ~ 3 min and muscle glycogen content which was 372 and 756 mmol·kg−1 dw in each leg following prior exercise and diet manipulations [29]. However, when a second bout was performed after a recovery period, with pre-exercise muscle glycogen concentrations lowered to 310 and 698 mmol·kg−1 dw, performance was impaired only in the low glycogen condition where post-exercise glycogen levels reached 125 mmol·kg−1 dw. This led the authors to conclude that above-normal muscle glycogen did not facilitate high-intensity exercise performance, whereas depletion below a certain threshold provoked impaired exercise tolerance. However, the glycogen manipulation was achieved through exhaustive exercise performed three- compared to one day prior to testing in the high and low glycogen legs, respectively, inducing a possible influence of persisting fatigue. Vandenberghe et al. [86] assessed the effect of elevated muscle glycogen stores (364 vs. 568 mmol·kg−1 dw pre-exercise) on muscle metabolism in an initial condition and repeated the same diet and exercise intervention in a second condition, expecting alterations of a similar magnitude, but observed no performance-enhancing effect in time-to-exhaustion at 125% VO2max. Similarly, Hargreaves et al. [30] observed no difference in 75-s exercise performance when muscle glycogen was manipulated (462 vs. 668 mmol·kg−1 dw pre-exercise), reaching 359 mmol·kg−1 dw post-exercise in the low glycogen condition. Thus, it seems that at least when muscle glycogen is only moderately altered, no effect is evident for continuous high-intensity performance. However, five other studies assessed the influence of glycogen-depleting exercise followed by diet manipulations without muscle biopsy sampling [76,77,78,79, 95]. In all these, time-to-exhaustion at 100–115% VO2max was substantially decreased (15–31%) in the low-carbohydrate trials. Moreover, the effect of enhanced carbohydrate intake with the purpose of elevating muscle glycogen content above resting levels was indirectly evaluated by the incorporation of a supercompensation condition [76,77,78,79, 89] and in only two investigations was a performance-enhancing effect observed [79, 89]. However, neither study was placebo-controlled and the order of exercise was not randomized by Maughan et al. [79]. Collectively, muscle glycogen seems to be important for continuous high-intensity exercise tolerance only if a certain degree of depletion is achieved, whereas loading the stores above normal levels imposes no consistent additional benefit. However, more research with measurements of muscle glycogen content is warranted.
5.2 Single and Repeated Sprint Ability
In three out of four studies with a measured lowering of muscle glycogen, performance declined in single or repeated sprint activities [31, 85, 93, 97]. For example, Balsom et al. [31] utilized 15 × 6-s sprints interspersed by 30-s of recovery and observed a 5% performance impairment in the last four exercise bouts in the low glycogen trial (180 vs. 397 mmol·kg−1 dw pre-exercise), reaching post-exercise glycogen values of 127 mmol·kg−1 dw, which is similar to findings by Gejl et al. [97]. Further, Rockwell et al. [93] performed repeated 60-s all-out efforts with 3-min recovery until a 30% decrease in average power and observed a nearly 40% shorter time-to-exhaustion when muscle glycogen was lowered (222 mmol·kg−1 dw pre-exercise and 118 mmol·kg−1 dw post-exercise). In contrast, Hargreaves et al. [85] observed no influence of altered muscle glycogen content on 30-s maximal cycling, but muscle glycogen content was only reduced to 350 mmol·kg−1 dw pre-exercise in the low condition. In line with this, Gejl et al. [69], observed no change in performance during 4 × 4-min supramaximal ergometer skiing time-trials with 45 min of recovery, with muscle glycogen levels of 575 and 383 mmol·kg−1 dw before the first- and the last bout, respectively.
In three additional studies, without muscle glycogen measurements, sprint performance deteriorated in low carbohydrate conditions [87, 88, 91], whereas one study found no change in performance, possibly explained by a low sample size [81]. Moreover, high-carbohydrate conditions were included in three investigations to elevate muscle glycogen stores, but no performance-improvement was observed in line with Hargreaves et al. [85]. Collectively, it appears that substantial reductions in muscle glycogen content is linked with impaired performance during both single and repeated sprint activities, whereas carbohydrate-loading seems to add no additional benefit, but the existing literature with actual muscle glycogen measurements is limited.
5.3 Assessments of Neuromuscular Function
No effects of lowered or elevated muscle glycogen content were observed in all but one investigation examining the relationship between glycogen content and neuromuscular function [75, 80, 83, 96, 99]. For example, Jacobs et al. [80] detected no differences in a muscle fatigue test consisting of repeated maximal isokinetic knee-extensor contractions when pre-exercise muscle glycogen was altered (205 vs. 412 vs. 812 mmol·kg−1 dw). Similarly, Symons et al. [75] performed quadriceps surface electrical stimulation at 50 Hz for 2 s, maximal voluntary isometric contractions, and a muscle fatigue test and no distinction in performance was observed despite marked differences in pre-exercise muscle glycogen storage (153 vs. 426 mmol·kg−1 dw). An equivalent pattern was reported by Skein et al. [96] also utilizing neuromuscular and muscle fatigue testing with repeated maximal contractions. In addition, Cheng and coworkers [99] observed no improved recovery of maximal voluntary- or electrically stimulated low- or high-frequency contractions by carbohydrate ingestion following exercise. Only one study reported altered neuromuscular performance in a purportedly lowered and super compensated muscle glycogen state, but without muscle biopsy sampling [82]. Hence, repeatedly stimulating the triceps surae muscle using trains at 20 Hz lasting 330 ms every s for 2 min resulted in a 7% reduction in performance in the low- and a 12% improvement in the high carbohydrate condition. In contrast, no effect was observed for trains at 10, 20, and 50 Hz or maximal voluntary contractions. Also during sustained isometric contractions, impaired performance was observed in two studies when muscle glycogen was lowered, however, effects of prior exercise were not accounted for [83, 84]. Finally, divergent findings appear for the capacity to perform resistance or power exercise in purpotedly lowered glycogen conditions as one study observed an impairment in total work capacity [98], whereas two studies did not show any effect [90, 94]. In a study by Leveritt et al. [92] a reduced performance was only observed for maximal isoinertial strength including multiple repetitions, but not in a limited series of brief isokinetic knee-extensions at different speeds, which likely poses less of a challenge to the glycogenolytic system.
In summary, no effects of muscle glycogen availability are observed when evaluating the performance of brief electrically or voluntarily induced single contractions, which may be explained by lower glycogenolytic stress in such brief contractions. Surprisingly, during the muscle fatigue tests, which included several sequential brief contractions, there were still no consistent effects of glycogen availability. Finally, divergent evidence is available for the impact of muscle glycogen content on resistance exercise capacity, and more research is needed to allow for firm conclusions.
6 Summary of the Relationship Between Muscle Glycogen Content and High-Intensity Performance
Collectively, it appears possible to produce maximal force for brief periods as in a single or limited series of maximal contractions in a lowered muscle glycogen state, whereas inconclusive evidence is available for resistance exercise capacity. In contrast, continuous or repeated high power outputs requiring maximal rates of glycogenolysis and producing large alterations in cellular metabolite and ion homeostasis, consistently results in impaired performance when glycogen is lowered. Moreover, it appears that a threshold for impaired performance of ~ 250 to 300 mmol·kg−1 dw is evident (see Fig. 5). This is consistent with results obtained from intermittent sporting activities where muscle glycogen has been linked to high-intensity exercise tolerance [43, 100,101,102]. Thus, the effects of lowered muscle glycogen may be important for end-game fatigue during team sports where muscle glycogen decreases substantially (below ~ 200 mmol·kg−1 dw) [19, 57, 102, 103]. Of note, these data represent whole-muscle glycogen content and do not delineate both fiber-type and subcellular heterogeneity in utilization as outlined above. Glycogen may also be critically lowered earlier during exercise in congested fixtures where a progressive reduction has been demonstrated in ice hockey and in situations of short recovery time, for example in soccer where a prolonged glycogen repletion pattern has been shown [70, 104, 105]. Moreover, athletes engaged in multiple daily high-intensity events may be prone to detrimental effects of lowered muscle glycogen content during subsequent exercise as well as athletes performing high-intensity training coupled with periods of energy restriction. On that note, it has been demonstrated that the rate of muscle glycogen resynthesis is elevated after high-intensity exercise during the initial stages of recovery (~ 0 to 2 h), likely attributable to elevated glycolytic intermediates and lactate production providing immediate substrate for glycogen resynthesis, at least transiently before returning to resting levels (for review see Pascoe et al. [106] and Jentjens et al. [107]).
Muscle glycogen levels in the low glycogen conditions in studies providing these values, while evaluating performance during continuous high-intensity exercise as well as single or repeated sprint ability compared to a normal glycogen control condition. * = reduced performance in the low glycogen condition (P ≤ 0.05). Full bars represent pre-exercise glycogen levels, whereas the striped area marks the amount of glycogen utilized in the studies providing these values. Area between dashed lines = approximate threshold for impaired exercise tolerance. Bangsbo et al. A = first exercise bout and Bangsbo et al. B = second exercise bout from Bangsbo et al. [29]
Importantly, several methodological limitations should be considered such as a lack of muscle glycogen measurements, placebo-control and non-randomized order of exercise. Moreover, the mode of glycogen-depleting exercise may be important since Jacobs et al. [108] reported that glycogen depletion of both slow- and fast-twitch quadriceps muscle was associated with attenuated maximal strength, whereas selective depletion of slow-twitch fibers did not impair performance. In the studies discussed above, prolonged exercise or a combination of prolonged and high-intensity exercise was applied. In addition, Karlsson et al. [109] found the deleterious effects of muscle glycogen depletion to be most pronounced in individuals with a high distribution of glycolytic fast-twitch fibers. Finally, the post-prandial state in which participants were tested differed which may influence blood glucose levels and affect exercise tolerance irrespective of muscle glycogen levels [110].
7 Mechanisms Linking Lowered Muscle Glycogen Content to Muscle Function
In the following sections suggested mechanisms delineating interactions between lowered muscle glycogen and muscle function will be discussed. These include altered substrate metabolism, Ca2+ regulation, muscle excitability, myofibrillar contractile function, and a brief discussion of other potential mechanisms.
7.1 Muscle Glycogen Content and Glycogenolytic/Glycolytic Rate
The temporal relationship between muscle glycogen content and exercise tolerance has traditionally been attributed to perturbations in energy status to preserve the ATP resynthesis rate required for optimal excitatory and contractile function provoked by depleted muscle glycogen stores during prolonged exercise [14, 32, 111]. In contrast, during high-intensity exercise, fatigue development manifests in advance of severe glycogen depletion with marked PCr degradation, H+ and phosphate accumulation and it has therefore been assumed that glycogen levels do not significantly affect energy metabolism under these conditions [12]. During prolonged exercise, the energy deficiency theory is supported by increased deamination of AMP to IMP and NH3 at the point of fatigue, indicative of increased reliance on the myokinase reaction including decreased pyruvate and tricarboxylic acid intermediates suggestive of inadequate energy supply [111,112,113,114]. On the contrary, no or only minor reductions in global levels of muscle ATP and non-depleted levels of PCr have been reported at fatigue during prolonged exercise, even in the presence of low glycogen levels [33, 111,112,113], which is in contrast to observations during high-intensity exercise where significant perturbations occur, especially in fast-twitch fibers [9, 11, 46, 56, 63]. Moreover, increases in IMP have been speculated to relate to the gradual activation of fast-twitch fibers during progressive exercise as even low-frequent stimulation induces major increases in IMP formation in rodent fast-twitch muscle despite sufficient glycogen availability [53, 115, 116]. However, increases in IMP occur in both slow- and fast-twitch fibers in humans, being most pronounced in glycogen-depleted fibers [61]. Further, Sahlin et al. [32] suggested that even small decreases in ATP, while not consistently observed at the whole-muscle level, may occur in restricted cell compartments or in specific glycogen-depleted fibers and result in substantial relative increases in ADP, AMP and Pi, which may affect muscle function rather than a decrease in ATP per se. This is in line with the previous results by Norman et al. [61] showing higher IMP accumulation in glycogen-depleted fibers and large PCr degradation in specific single fibers in human skeletal muscle indicating substantial local energy deficiency [62]. Thus, global measures of energy homeostasis may be inadequate for describing a link between muscle glycogen and fatigue since perturbations in individual fibers or within microenvironments in the highly structured muscle cells may occur. Notably, this may be relevant for high-intensity exercise since local energy restrictions caused by substrate depletion in specific areas could be important despite only moderately lowered global levels. Further, local energy disruptions may be augmented by the increasing muscle acidosis accumulating during high-intensity exercise as the combination of muscle acidosis and increased Pi has been suggested to act synergistically to exacerbate fatigue development [117]. However, the rate of H+ accumulation would be expected to be lower in a glycogen-depleted condition due to a potentially reduced muscle energy turnover and earlier onset of fatigue. For example, Bangsbo et al. [118], demonstrated that time-to-exhaustion, but also muscle H+ accumulation and absolute H+ values, were lower at exhaustion when repeating high-intensity exercise with lowered muscle glycogen content after a one hour recovery period.
During prolonged exercise muscle glycogen utilization rates have been demonstrated to associate with initial muscle glycogen concentrations in nearly all studies [6, 119,120,121,122], with few exceptions [123]. At high initial glycogen levels, glycogen phosphorylase activity is likely increased, whereas it is unclear whether low initial glycogen levels per se or other factors such as increased free fatty acid availability or hormonal alterations following low-carbohydrate diets (typically with a high-fat content) are the dominant factors that affects metabolism [10, 124, 125]. Moreover, Stellingwerff et al. [126] reported increased fat metabolism and a decrease in glycogenolysis after a 5-day high-fat diet despite restoration of carbohydrate stores during a final days diet. In vitro studies attempting to circumvent this, support a link between muscle glycogen content and glycogenolytic rate in some [127,128,129], but not all studies [130, 131]. In contrast, the glycogenolytic rate appears to be regulated irrespective of initial glycogen level during high-intensity exercise in vivo [75, 83, 86, 132,133,134,135], at least when muscle glycogen stores are not fully depleted. For example, Ren et al. [134] demonstrated that muscle glycogen breakdown was unaffected by initial glycogen content in the range of 155–350 mmol·kg−1 dw when imposing intense electrical stimulation to the quadriceps muscle which is similar to findings by Spencer et al. [135] during exercise at 95% VO2max despite elevated muscle IMP concentrations in a low glycogen condition. However, time-to-exhaustion was markedly deteriorated and it is difficult to ascertain whether a reduced glycogenolytic rate in the final stages of exercise affected performance [135]. Jacobs et al. [80] observed lower muscle lactate accumulation during intense knee-extensor exercise only when glycogen was severely lowered (~ 170 mmol·kg−1 dw), but this was not replicated in a subsequent study by Symons et al. [75] applying the same exercise modality. Collectively, a discrepancy exists for altered blood or muscle lactate accumulation during high-intensity exercise as some [76, 80, 88, 91, 95, 136], but not all studies support a relationship with muscle glycogen [75, 81, 85, 87, 137]. Nonetheless, changes in lactate concentrations may be a product of increased uptake by other tissues rather than a decreased rate of production and/or reflective of a lower total work performed and may therefore be a mediocre predictor of glycolytic rate [29].
The apparent discrepancy between prolonged and high-intensity exercise may be related to the rate of glycogen utilization during exercise which is ~ 0.5 and ~ 5 mmol glycosyl units·kg−1 dw·min−1 at 30 and 90% VO2max, respectively, but increases markedly to ~ 250 to 300 mmol glycosyl units·kg−1 dw·min−1 during maximal exercise at ~ 300 VO2max which is only sustainable for a few seconds [9, 11, 44, 59]. Thus, during sub-maximal exercise in a low glycogen condition, it may be possible to adapt metabolism to fuel availability and rely more on FFA oxidation and plasma glucose extraction, whereas high-intensity exercise demands maximal activation of the glycogenolytic system [10, 125, 138, 139]. This is triggered by marked metabolic disturbances, including elevated levels of ADP and Pi, AMP, IMP and NH3, in association with increased Ca2+ transients and possible regulation from muscle H+ concentration [50, 130, 138, 140,141,142]. Accordingly, Km values of phosphorylase b and a for glycogen are extremely low, i.e. less than 3 mmol glucosyl units·l−1 and it is, therefore, conceivable that glycogen concentration per se plays little role in limiting the rate of glycogenolysis [143]. However, due to the heterogeneous distribution of glycogen in muscle fibers, it cannot be excluded that subsaturating levels of glycogen can occur in specific cell areas which is difficult to capture with global measures of glycogenolytic rate.
In summary, energy deficiency caused by a decelerated glycogenolytic/glycolytic rate in a condition of low muscle glycogen may be implicated in fatigue development during high-intensity exercise. However, no conclusive evidence is presently available, and it is conceivable that energy deficiency may only cause a problem if muscle glycogen is severely lowered at the whole-muscle level or when distinct areas or individual fibers become depleted. Accordingly, the link between muscle glycogen and muscle fatigue, as well as underlying mechanisms explaining such coupling is not well understood. It has been proposed that muscle glycogen can affect several steps in E-C coupling including the propagation of action potentials along the sarcolemma and into the T-system, triggering Ca2+ release and initiation of crossbridge cycling [14] (see Fig. 6). Evidence for alterations in these steps will be discussed below.
Simplified overview of possible interactions between muscle glycogen storage size and muscle function through direct associations between muscle glycogen and steps in E–C coupling and cross-bridge cycling (e.g. localization-specific metabolic perturbations and/or regulation from glycogen storage size) and/or indirectly through reduced glycogenolytic rate and impaired whole-muscle energy homeostasis including accelerated metabolite accumulation. NKA = Na+-K+-ATPase
7.2 Muscle Glycogen and Muscle Excitability
Muscle excitability is paramount for muscle contractility [13] and Na+-K+-ATPases are important regulators of excitability when the homeostasis of the cell interior and resting membrane potential is challenged by large Na+ and K+ fluxes during high-intensity exercise [13, 144, 145]. The extracellular K+ accumulation increases with exercise intensity reaching interstitial levels of 10–14 mM [144, 146, 147]. At such K+ concentrations slow-inactivation of voltage-gated Na+ channels may occur, impairing action-potential propagation and muscle function [148,149,150], although several mechanisms interact during exercise to counteract the depressive effects of elevated extracellular levels of K+ [151,152,153]. In this regard, multiple studies have demonstrated a downturn in maximal Na+-K+-ATPase activity following both prolonged and intense exercise [154,155,156,157,158,159,160] (for review see McKenna et al. [18]) although contradictory findings and methodological questions have been raised for the in vitro measurements of Na+-K+-ATPase activity [161,162,163,164,165]. Nonetheless, a possible decrease in Na+-K+-ATPase activity following exhaustive exercise may be partly associated with lowered muscle glycogen levels (and the inability to supply ATP locally) and consequently an impaired ability of muscle fibers to regulate ion fluxes. This interplay is noteworthy since it has been demonstrated that Na+-K+-ATPases in the T-system of skeletal muscle, where ionic perturbations may be most severe during exercise [149], preferentially utilize ATP derived from glycolysis [36, 166, 167]. Thus, stimulation of glycolytic ATP production in mechanically skinned fibers decreased the repriming period in partly depolarized fibers, indicative of increased Na+-K+-ATPase activity, whereas the addition of pyruvate as substrate for the TCA cycle did not elicit any up-regulations in excitability [36]. Further, inhibition of glycolysis has been shown to increase intracellular Na+ concentrations, likewise indicative of attenuated Na+-K+-ATPase activity, whereas blockage of Na+-K+-ATPases by ouabain substantially lowers the glycogenolytic/glycolytic rate [167, 168]. Furthermore, enzymatical removal of glycogen or inhibition of glycogen phosphorylase has been shown to increase the repriming period in rat fast-twitch muscle, even despite globally normal ATP concentrations [34, 35]. This supports the possibility of glycogen functioning as a direct regulator of muscle excitability, or alternately, that muscle glycogen may be essential for supplying ATP to the T-system and triad junctions with limited diffusional capacity and a large density of Na+-K+-ATPases [34, 35, 64]. However, from a mechanistic perspective, it is unclear whether altered Na+-K+ fluxes and muscle excitability are directly associated with changes in Na+-K+-ATPase activity since other ion fluxes partake in the control of muscle excitability. Thus, muscle-specific chloride channels (ClC-1) exert a counter-regulatory effect on muscle excitability during exercise (for reviews see Baekgaard et al. [169] and Imbrici et al. [170]). The ClC-1 channels are finely regulated by the metabolic state of the muscle and it is therefore possible that muscle glycogen can be implicated in the activation/deactivation of these channels. However, direct experimental evidence to support a potential relationship to muscle glycogen stores is required [169].
In summary, changes in muscle excitability, likely influenced by altered Na+-K+-ATPase activity in concert with possible perturbations in other ion channel systems may precipitate muscle fatigue during high-intensity exercise in a glycogen-depleted state, although more direct evidence in exercising humans and on exact regulatory mechanisms is warranted.
7.3 Muscle Glycogen and Ca2+ Regulation
In skeletal muscle, Ca2+ released from the SR is an integral part of muscle function through initiation of cross-bridge cycling and activation of metabolism. Although Ca2+ release as such is not an energy-consuming process, glycogenolytic complexes including glycogen-regulating and glycolytic enzymes are associated with the SR, advocating for a connection between muscle glycogen metabolism and Ca2+ regulation [65, 66, 171,172,173,174]. Accordingly, the calcium release channels (RyR1) are modulated by ATP levels activating the channels by directly binding to one or more sites at the RyR1 proteins [175,176,177,178]. Accumulation of the byproducts of ATP hydrolysis during muscle contractions (especially ADP and AMP) on the other hand acts as competitive weak agonists interfering with optimal ATP and RYR1 associations, changing the open probability of these channels. Indeed, experiments in humans [28, 97, 105, 179] and animal models [27, 37,38,39, 73, 74] with one exception [180] have demonstrated that amended Ca2+ kinetics may be an important determinant linking lowered muscle glycogen content to deteriorated muscle function. For example, early experiments by Chin and Allen [27] applied electrical stimulation to intact mouse skeletal muscle to deplete the muscle glycogen stores. Subsequent recovery, in absence or presence of glucose resulted in only partial recovery of force and a sustained lowering of glycogen in the glucose-free trial. In contrast, full recovery of force and substantial glycogen resynthesis was observed in the glucose condition accompanied by differences in Ca2+ release [27]. In later human experiments involving elite cross-country skiers Ørtenblad et al. [28] and subsequently Gejl et al. [97] confirmed that muscle glycogen was linked with Ca2+ kinetics as recovery with or without glucose resulted in substantial differences in glycogen levels and SR Ca2+ release rate. Specifically, intramyofibrillar glycogen was linked with Ca2+ kinetics, and not subsarcolemmal nor intermyofibrillar stores [28]. The association of intramyofibrillar glycogen and SR Ca2+ release rate has subsequently been confirmed in vitro by single fiber measurements [39, 67]. In a study by Nielsen et al. [39] a positive relationship between intramyofibrillar glycogen content and exercise capacity and an inverse link between intermyofibrillar glycogen content and half-relaxation time was demonstrated. This suggests that Ca2+ uptake, which in contrast to Ca2+ release is an energy-consuming process, can also be adversely impaired by lowered muscle glycogen. Moreover, this intriguingly points to distinct effects of specific muscle glycogen storage sites. In support, an accelerated reduction in Vmax of the Ca2+ ATPase and both Ca2+ release and uptake has been demonstrated in exercising humans when initiating exercise with lowered muscle glycogen [179]. In more recent observations by Gejl et al. [97], peak power output during repeated high-intensity exercise and SR Ca2+ release was impaired in a low glycogen condition, further supporting a link between muscle glycogen, Ca2+ kinetics and high-intensity exercise performance. In this regard, a critical threshold of ~ 250 to 300 mmol·kg−1 dw has been suggested to compromise calcium kinetics which fits well with the observed threshold for impaired exercise performance observed in the present review and previous observations of increased cell signaling below this level of glycogen storage [28, 97, 179, 181]. Importantly, muscle glycogen may impair muscle function independent of muscle cell global ATP level, as demonstrated in experiments with mechanically skinned fibers where global ATP can be kept high and constant, while glycogen levels are manipulated [34, 35, 39, 73]. For example, the ability of mechanically skinned toad fibers to respond to T-system depolarization was impaired in a low glycogen condition despite the bathing solution being rich in ATP and PCr [73]. This suggests either a non-metabolic role of muscle glycogen or that muscle glycogen may exert a direct localization–specific metabolic effect through storage of muscle glycogen in specific subcellular areas, providing immediately available energy for ATP resynthesis, which may be critical for muscle function [64]. This may serve as a potential feedback mechanism between muscle glycogen storage size and muscle excitability and SR Ca2+ release to prevent excessive ATP depletion of the cell and protect intracellular homeostasis [28]. Alternately, a possible structural role of muscle glycogen has been proposed, as glycogen depletion may result in dissociation of the glycogenolytic complexes from the SR, changing its structural integrity and/or through phosphorylation/de-phosphorylation changes of the Ca2+ release channels and glycogenolytic enzymes [174, 182,183,184]. Accordingly, a regulatory phosphatase protein subunit appears to couple these complexes to the SR [185]. Moreover, evidence of intracellular redistribution of the active form of glycogen phosphorylase has been suggested, acting as a safety mechanism to inhibit glycogenolysis when muscle glycogen levels are critically low [186]. Finally, AMP-activated protein kinase (AMPK) has a glycogen binding domain, and it has been hypothesized that glycogen depletion results in inhibition of the glycogen-pool of AMPK, suggesting that energy availability and energy-sensing are interrelated, although these hypotheses have not yet been thoroughly studied [187,188,189,190,191,192].
In summary, substantial evidence indicates an important modulating effect of muscle glycogen content on SR Ca2+ regulation and muscle function, either through a direct metabolic role, possibly in relation to compartmentalized energy turnover and/or indirectly through feedback regulation from muscle glycogen metabolism. It is therefore credible, that altered SR Ca2+ kinetics can affect the muscle fatigue response during high-intensity exercise although exact mechanisms remain inconclusive.
7.4 Muscle Glycogen and Myofibrillar Function
The majority of the literature describing the effects of low glycogen has been focused on the relationship between muscle glycogen and key steps in the E-C coupling preceding the actual myofibrillar contraction. However, a decline in muscle glycogen at the whole-muscle level or in local myofibrillar fractions (inter and intramyofibrillar glycogen) could reduce the ATP provision for myosin ATPase and/or accelerate the formation of Pi which has been demonstrated to exert substantial inhibitory effects on the contractile machinery [14, 17]. Thus, muscle glycogen depletion may be hypothesized to affect the contractile function if lowered muscle glycogen is metabolically coupled to muscle fatigue. In a study by Chin et al. [27] an association was observed between changes in muscle glycogen and alterations in Ca2+ sensitivity and maximal Ca2+-activated force-generating capacity of myofibrils from mouse skeletal muscle. The magnitude of this alteration of myofibrillar function was similar in the glycogen-depleted state as in the baseline condition but occurred markedly faster during the contraction protocol suggesting that reduced ATP provision and PCr depletion were accelerated. Similarly using mouse skeletal muscle, Helander et al. [37] reported a delayed decrease in myofibrillar Ca2+ sensitivity after recovery in the presence of glucose, which is likely to be mediated via increased muscle glycogen. Contrasting these findings others have failed to observe any decline in maximally Ca2+ activated force in a lowered muscle glycogen condition using mechanically skinned fibers from cane toad [38, 73] or rat EDL muscle [74]. However, in two of these latter studies, the global levels of ATP and PCr were maintained high and constant [73, 74], whereas in the third study glycogen was only moderately lowered and measurements of intracellular Mg2+, which are thought to reflect intracellular ATP levels, were unchanged [38]. Thus, differences in diffusional restrictions compared to the T-system and restricted triadic junctions may have enabled cytosolic ATP and PCr availability to support myofibrillar function during these experiments. Therefore, more investigations are needed measuring myofibrillar function in conditions of low glycogen especially in human single fibers to provide unequivocal conclusions.
Collectively, low muscle glycogen may affect myofibrillar function through metabolite accumulation secondary to low glycogen levels, whereas the effects of localized energy deficiency is inadequately described and not fully understood.
7.5 Other Potential Factors
In addition to the above interactions between muscle glycogen and muscle function that may affect performance during high-intensity exercise other related mechanisms have been suggested. Thus, central fatigue in response to lowered muscle glycogen levels has been proposed based on altered self-paced performance during prolonged- as well as intermittent high-intensity exercise in lowered glycogen conditions, even in situations where subjects were unaware of the fact that muscle glycogen was manipulated [96, 193]. However, these links have not yet been well-examined and may in part be explained by hypoglycemia-related central fatigue appearing concomitant with decreased muscle glycogen levels [96, 110, 194, 195]. Interestingly, reductions in brain glycogen have been demonstrated in animals model which may be another mechanism by which glycogen can affect the central nervous system irrespective of muscle glycogen levels although no evidence for such a link is available in exercising humans [196, 197].
8 Conclusion
In conclusion, lowering skeletal muscle glycogen content can alter muscle function and provoke impairments in performance during high-intensity exercise, whereas elevated muscle glycogen stores provide no additional performance-enhancing benefit. However, more high-quality studies in exercising humans are needed to confirm these relationships. The apparent exacerbated muscle fatigue in a lowered glycogen condition is likely multifactorial and may associate with multiple key steps in the E-C coupling, such as modified cell excitability and Ca2+ kinetics, and may be mediated by a direct metabolic role (provision of ATP) likely through localization–specific energy metabolism and/or indirectly through feedback regulation from muscle glycogen stores, including a possible link to the central nervous system. Accordingly, depletion of individual muscle fibers and specific subcellular compartments may be essential in explaining the accelerated fatigue development in a lowered glycogen condition, even in advance of whole-muscle glycogen depletion.
9 Future Research
Since many questions remain open, future research should seek to expand these knowledge gaps through experiments further detailing the regulation of muscle function and metabolism in relation to muscle glycogen storage size. Thus, experiments concerning systemic whole-body exercise to fiber-type specific, whole-muscle and single fiber measurements, including expanded analyses of subcellular substrate metabolism and protein regulation/translocation and even measures of brain glycogen metabolism and central fatigue responses would be interesting research areas. Suggested key areas could be human single fiber metabolism and fatigue responses of slow and fast-twitch fibers as well as measures of in vivo metabolism using nuclear magnetic resonance spectroscopy of skeletal muscle and brain tissue. Specifically, the role and utilization of the compartmentalized glycogen pools, for distinct ATPases and steps in E-C coupling, warrant further investigation. Also, placebo-controlled trials with actual measurements of muscle glycogen metabolism are evidently needed to unequivocally determine the effect of muscle glycogen on high-intensity exercise performance.
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We would like to acknowledge the contribution to the current project from the Danish Ministry of Culture, the Danish Elite Sports Organization Team Danmark and by The Novo Nordisk Foundation grant to Team Danmark (the PRoKIT research network).
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The work was supported by the Danish Ministry of Culture (Grant no. FPK.2016-0054), the Danish Elite Sports Organization Team Danmark and by The Novo Nordisk Foundation grant to Team Danmark.
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JFV-L and MM conceived the article. JFV-L conducted the literature search and wrote the first manuscript drafts. All authors made substantial contributions to the conception of the manuscript including critical revisions and contributions. All authors read and approved the final manuscript.
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Vigh-Larsen, J.F., Ørtenblad, N., Spriet, L.L. et al. Muscle Glycogen Metabolism and High-Intensity Exercise Performance: A Narrative Review. Sports Med 51, 1855–1874 (2021). https://doi.org/10.1007/s40279-021-01475-0
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DOI: https://doi.org/10.1007/s40279-021-01475-0