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Cited by 252Muscle metabolism and nutritionCardiovascular and exercise physiologyMetabolism, Diabetes, and Cancer

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Regulation of Muscle Glycogen Metabolism during Exercise: Implications for Endurance Performance and Training Adaptations

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Hearris, Mark, Hammond, Kelly, Fell, J., Morton, James·2018·Nutrients
DOI 10.3390/nu10030298PMC PMC5872716
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Abstract

Since the introduction of the muscle biopsy technique in the late 1960s, our understanding of the regulation of muscle glycogen storage and metabolism has advanced considerably. Muscle glycogenolysis and rates of carbohydrate (CHO) oxidation are affected by factors such as exercise intensity, duration, training status and substrate availability. Such changes to the global exercise stimulus exert regulatory effects on key enzymes and transport proteins via both hormonal control and local allosteric regulation. Given the well-documented effects of high CHO availability on promoting exercise performance, elite endurance athletes are typically advised to ensure high CHO availability before, during and after high-intensity training sessions or competition. Nonetheless, in recognition that the glycogen granule is more than a simple fuel store, it is now also accepted that glycogen is a potent regulator of the molecular cell signaling pathways that regulate the oxidative phenotype. Accordingly, the concept of deliberately training with low CHO availability has now gained increased popularity amongst athletic circles. In this review, we present an overview of the regulatory control of CHO metabolism during exercise (with a specific emphasis on muscle glycogen utilization) in order to discuss the effects of both high and low CHO availability on modulating exercise performance and training adaptations, respectively.

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Figure 1 Variations in muscle glycogen storage according to fatigue status, training status and dietary carbohydrate (CHO) intake (data are compiled from males only and from several studies including Taylor et al. [30]; Bartlett et al. [31]; Arkinstall et al. [32]; Gollnick et al. [24]; Coyle et al. [8]).
Figure 1 Variations in muscle glycogen storage according to fatigue status, training status and dietary carbohydrate (CHO) intake (data are compiled from males only and from several studies including Taylor et al. [30]; Bartlett et al. [31]; Arkinstall et al. [32]; Gollnick et al. [24]; Coyle et al. [8]).CC BY · PubMed Central
Figure 2 Overview of CHO metabolism and main control points. Key regulatory enzymes are well recognized as phosphorylase (PHOS), hexokinase (HK), phosphofructokinase (PFK), lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH). Additionally, the rate of muscle glucose uptake can also determine the flux through glycolysis. Abbreviations: ADP, Adenosine diphosphate; AK, Adenylate kinase; AKT, Protein kinase B; AMP, Adenosine monophosphate; ATP, Adenosine triphosphate; Ca2+, Calcium; CHO, Carbohydrate; CK, Creatine kinase; Cr, Creatine; CS, Citrate synthase; ETC, Electron transport chain; G-1-P, Glucose-1-phosphate; G-6-P, Glucose-6-phosphate; Glu, Gluose; GLUT4, Glucose transporter 4; H+, Hydrogen ion; H2O, water; IRS-1, Insulin receptor substrate 1; HK, Hexokinase; LDH, Lactate dehydrogenase; O2, Oxygen; NAD, Nicotinamide adenine dinucleotide; TCA cycle, Tricarboxylic acid cycle; Pi, phosphate; PCr, Phosphocreatine; PFK, Phosphofructokinase; PhK, Phosphorylase kinase; PHOS, Glycogen phosphorylase; PI3-K, Phosphoinositide 3-kinase.
Figure 2 Overview of CHO metabolism and main control points. Key regulatory enzymes are well recognized as phosphorylase (PHOS), hexokinase (HK), phosphofructokinase (PFK), lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH). Additionally, the rate of muscle glucose uptake can also determine the flux through glycolysis. Abbreviations: ADP, Adenosine diphosphate; AK, Adenylate kinase; AKT, Protein kinase B; AMP, Adenosine monophosphate; ATP, Adenosine triphosphate; Ca2+, Calcium; CHO, Carbohydrate; CK, Creatine kinase; Cr, Creatine; CS, Citrate synthase; ETC, Electron transport chain; G-1-P, Glucose-1-phosphate; G-6-P, Glucose-6-phosphate; Glu, Gluose; GLUT4, Glucose transporter 4; H+, Hydrogen ion; H2O, water; IRS-1, Insulin receptor substrate 1; HK, Hexokinase; LDH, Lactate dehydrogenase; O2, Oxygen; NAD, Nicotinamide adenine dinucleotide; TCA cycle, Tricarboxylic acid cycle; Pi, phosphate; PCr, Phosphocreatine; PFK, Phosphofructokinase; PhK, Phosphorylase kinase; PHOS, Glycogen phosphorylase; PI3-K, Phosphoinositide 3-kinase.CC BY · PubMed Central
Figure 3 Schematic overview of the potential exercise-nutrient sensitive cell signalling pathways regulating the enhanced mitochondrial adaptations associated with training with low CHO availability. Reduced muscle glycogen and exogenous glucose availability enhance both AMPK and p38MAPK phosphorylation which results in activation and translocation of PGC-1α and p53 to the mitochondria and nucleus. Upon entry into the nucleus, PGC-1α co-activates additional transcription factors, (i.e., NRF1/2) to increase the expression of COX subunits and Tfam as well as auto-regulating its own expression. In the mitochondria, PGC-1α co-activates Tfam to coordinate the regulation of mtDNA and induces expression of key mitochondrial proteins of the electron transport chain, e.g., COX subunits. Similar to PGC-1α, p53 also translocates to the mitochondria to modulate Tfam activity and mtDNA expression and to the nucleus where it functions to increase the expression of proteins involved in mitochondrial fission and fusion (DRP-1 and MFN-2) and electron transport chain protein proteins. Exercising in conditions of reduced CHO availability increases adipose tissue and intramuscular lipolysis via increased circulating epinephrine concentrations. The resulting elevation in FFA activates the nuclear transcription factor, PPARδ, to increase expression of proteins involved in lipid metabolism, such as CPT-1, PDK4, CD36 and HSL. However, consuming pre-exercise meals rich in CHO and/or CHO during exercise can down-regulate lipolysis (thereby negating FFA mediated signalling) as well as reducing both AMPK and p38MAPK activity, thus having negative implications for downstream regulators. High fat feeding can also modulate PPARδ signalling and up-regulate genes with regulatory roles in lipid metabolism (and down-regulate CHO metabolism), though high fat diets may also reduce muscle protein synthesis via impaired mTOR-p70S6K signalling, despite feeding leucine rich protein. Abbreviations: 4EBP1; eukaryotic translation initiation factor 4E-binding protein 1, AMPK; AMP-activated protein kinase, CHO; carbohydrate, COX; cytochrome c oxidase, CPT-1; carnitine palmitoyltransferase 1, Drp1; dynamin-related protein 1, FA; fatty acid, FABP; fatty acid binding protein, GLU; glucose, HSL; hormone sensitive lipase, IMTG; intramuscular triglycerides, Mfn2; mitofusion-2, mTORC1; mammalian target of rapamycin complex 1, p38 mitogen-activated protein kinase, p70S6K; ribosomal protein S6 kinase, PDK4; pyruvate dehydrogenase kinase 4, PGC-1α; peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PPARδ; peroxisome proliferator-activated receptor, Tfam; mitochondrial transcription factor A.
Figure 3 Schematic overview of the potential exercise-nutrient sensitive cell signalling pathways regulating the enhanced mitochondrial adaptations associated with training with low CHO availability. Reduced muscle glycogen and exogenous glucose availability enhance both AMPK and p38MAPK phosphorylation which results in activation and translocation of PGC-1α and p53 to the mitochondria and nucleus. Upon entry into the nucleus, PGC-1α co-activates additional transcription factors, (i.e., NRF1/2) to increase the expression of COX subunits and Tfam as well as auto-regulating its own expression. In the mitochondria, PGC-1α co-activates Tfam to coordinate the regulation of mtDNA and induces expression of key mitochondrial proteins of the electron transport chain, e.g., COX subunits. Similar to PGC-1α, p53 also translocates to the mitochondria to modulate Tfam activity and mtDNA expression and to the nucleus where it functions to increase the expression of proteins involved in mitochondrial fission and fusion (DRP-1 and MFN-2) and electron transport chain protein proteins. Exercising in conditions of reduced CHO availability increases adipose tissue and intramuscular lipolysis via increased circulating epinephrine concentrations. The resulting elevation in FFA activates the nuclear transcription factor, PPARδ, to increase expression of proteins involved in lipid metabolism, such as CPT-1, PDK4, CD36 and HSL. However, consuming pre-exercise meals rich in CHO and/or CHO during exercise can down-regulate lipolysis (thereby negating FFA mediated signalling) as well as reducing both AMPK and p38MAPK activity, thus having negative implications for downstream regulators. High fat feeding can also modulate PPARδ signalling and up-regulate genes with regulatory roles in lipid metabolism (and down-regulate CHO metabolism), though high fat diets may also reduce muscle protein synthesis via impaired mTOR-p70S6K signalling, despite feeding leucine rich protein. Abbreviations: 4EBP1; eukaryotic translation initiation factor 4E-binding protein 1, AMPK; AMP-activated protein kinase, CHO; carbohydrate, COX; cytochrome c oxidase, CPT-1; carnitine palmitoyltransferase 1, Drp1; dynamin-related protein 1, FA; fatty acid, FABP; fatty acid binding protein, GLU; glucose, HSL; hormone sensitive lipase, IMTG; intramuscular triglycerides, Mfn2; mitofusion-2, mTORC1; mammalian target of rapamycin complex 1, p38 mitogen-activated protein kinase, p70S6K; ribosomal protein S6 kinase, PDK4; pyruvate dehydrogenase kinase 4, PGC-1α; peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PPARδ; peroxisome proliferator-activated receptor, Tfam; mitochondrial transcription factor A.CC BY · PubMed Central

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Metadata

Authors
Hearris, M., Hammond, K., Fell, J., & Morton, J.
Affiliations
Liverpool John Moores University (GB)
Corresponding author
Morton, James
ORCID
Venue
Nutrients
Publisher
MDPI AG
Published
2018-03-02
Volume
10
Issue
3
Pages
298
ISSN
2072-6643 (ISSN-L)
DOI
10.3390/nu10030298
PMC
PMC5872716
OpenAlex
W2792934062
Cited by
252
References
120
Citations by year
2026: 30 · 2025: 31 · 2024: 34 · 2023: 26 · 2022: 38 · 2021: 40 · 2020: 27 · 2019: 17 · 2018: 9
FWCI
2.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Nutrients (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Liverpool John Moores University (acceptedVersion)
  • e-space (Manchester Metropolitan University) (acceptedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
GlaxoSmithKline
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
  • Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
muscle glycogen metabolism, glycogenolysis, carbohydrate oxidation, endurance performance, training effects, carbohydrate availability, glycogen storage, allosteric regulation, hormonal regulation, exercise intensity
MeSH terms
Adaptation, Physiological, Animals, Dietary Carbohydrates, Energy Metabolism, Glycogen, Humans, Muscle Contraction, Oxidation-Reduction, Phenotype, Physical Endurance, Signal Transduction, Muscle, Skeletal, Diet, Carbohydrate-Restricted

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