Abstract
Viewing metabolism through the lens of exercise biology has proven an accessible and practical strategy to gain new insights into local and systemic metabolic regulation. Recent methodological developments have advanced understanding of the central role of skeletal muscle in many exercise-associated health benefits and have uncovered the molecular underpinnings driving adaptive responses to training regimens. In this Review, we provide a contemporary view of the metabolic flexibility and functional plasticity of skeletal muscle in response to exercise. First, we provide background on the macrostructure and ultrastructure of skeletal muscle fibres, highlighting the current understanding of sarcomeric networks and mitochondrial subpopulations. Next, we discuss acute exercise skeletal muscle metabolism and the signalling, transcriptional and epigenetic regulation of adaptations to exercise training. We address knowledge gaps throughout and propose future directions for the field. This Review contextualizes recent research of skeletal muscle exercise metabolism, framing further advances and translation into practice.
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Change history
21 July 2023
In the version of this article originally published, in the Glossary definition for ‘Adrenoceptor’, ‘Transmembrane G-protein-coupled adrenergic receptors’ now reads as ‘Adrenergic transmembrane G-protein-coupled receptors’. In the figure legends for Figs. 1a and 2c, citations to the section ‘Acute exercise metabolism in skeletal muscle’ mistakenly named the section as ‘Acute exercise muscle metabolism’. Under the ‘Oxygen-dependent exercise metabolism’ subsection, in the third sentence of the first paragraph, H2O2 was incorrectly defined as ‘superoxide’ rather than ‘hydrogen peroxide’. In the same subsection, in the paragraph beginning ‘Muscle lipid metabolism…’, the ‘post-exercise plasma metabolome’ was initially stated to be the ‘post-exercise serum metabolome’ in the second sentence. Furthermore, some proteins in the article were missing mentions of their standard names and/or definitions from UniProt, which have now been added: ‘SLC25A12’ has been added for ‘AGE’, ‘mitochondrial 2-oxoglutarate/malate carrier, M2OM’ for ‘MOE’, and ‘AATM’ for ‘mAspAT’. In addition, a typographical error in the sentence beginning ‘This occurs through a muscle…’ in Box 4 caused ‘PPARα/PPARδ’ to read as ‘PPAα/δ’. Similarly, in the last paragraph of the ‘The post-exercise transcriptome’ subsection, ‘45S pre-rRNA’ was incorrectly written as ‘pre-45S rRNA’ in the second sentence. Lastly, the supplementary file has been exchanged with an updated version showing corrected positioning of myosin headgroups in their relaxed conformations in Supplementary Fig. 2. The updates are made in the HTML and PDF versions of the article.
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Acknowledgements
The authors apologize to all colleagues whose work could not be included owing to space constraints. The authors thank M. Karlén for preparation of the artwork in the supplementary figures. K.A.M. was supported by the National Institutes of Health (NIH R00 AG063994). K.A.D. was supported by Deutsches Zentrum für Diabetesforschung (2020/21). J.R.Z. was supported by the Swedish Research Council (Vetenskapsrådet) (2015-00165), the Swedish Research Council for Sport Science (P2022-0013, P2023-0093) and the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900).
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Glossary
- Adrenoceptor
-
Adrenergic transmembrane G-protein-coupled receptors (GPCRs) that mediate the actions of the endogenous catecholamines adrenaline and noradrenaline. There are nine subtypes of adrenoceptors: α1A, α1B, α1D, α2A, α2B, α2C, β1, β2 and β3. The α2A and α2C adrenoceptors regulate presynaptic neurotransmitter release from central adrenergic and peripheral sympathetic nerves.
- Ergogenic
-
A performance-enhancing effect.
- Hypertrophy
-
Typically refers to an increase in the cross-sectional area (or radial growth) of muscle fibres, resulting in gains of skeletal muscle mass in response to mechanical loading activities, such as resistance exercise.
- Ketone body
-
A lipid-derived, water-soluble, organic compound produced in the liver that can be used as an alternative energy source by extra-hepatic tissues — predominantly the brain, but also heart and skeletal muscle.
- Maximal oxygen consumption
-
(\(\mathop{{\rm{V}}}\limits^{.}\)O2max). The maximum volume of oxygen (ml kg−1 min−1) that can be inspired and utilized during exhaustive exercise, such that the value (\(\mathop{{\rm{V}}}\limits^{.}\)O2) plateaus despite increasing workloads. \(\mathop{{\rm{V}}}\limits^{.}\)O2max is a measure of aerobic or cardiorespiratory fitness and is commonly used to standardize exercise intensity for clinical trials (for example, x% of \(\mathop{{\rm{V}}}\limits^{.}\)O2max).
- Mitophagy
-
A specific form of lysosome-dependent catabolism (autophagy), through which damaged mitochondria are selectively removed. Mitophagy of the mitochondrial reticulum has an essential role in maintaining cellular energy homeostasis.
- Muscle spindles
-
Structures embedded in most mammalian skeletal muscles that continuously relay proprioceptive information regarding muscle length and movement to the central nervous system. Muscle spindles consist of intrafusal muscle fibres enclosed within a capsule layer and are distinct from the extrafusal muscle fibres discussed in this Review.
- Non-esterified fatty acids
-
(NEFAs). A metabolic substrate utilized by muscle at rest and in an intensity-dependent manner during exercise.
- Peak-twitch torque
-
The force produced by muscle (through a moment arm) evoked by a single electrical stimulation from, for example, applied electrodes.
- Phosphagen system
-
A rapid energy-producing pathway comprising the ATP regenerating adenylate kinase (ADP + ADP ⇌ ATP + AMP) and creatine kinase (CrP + ADP ⇌ ATP + Cr) reactions. Of these reactions, creatine kinase has a greater capacity for ATP resynthesis in muscle due to the availability of creatine phosphate stores.
- Proprioceptive
-
Able to sense intrinsic information regarding bodily position and locomotion. The primary proprioceptive sensory organ of the body is the muscle spindle.
- Proton-motive force
-
The proton electrochemical gradient in mitochondria consisting of an electrical charge gradient (also known as the ‘membrane potential’) and a pH gradient. The proton-motive force is generated by the proton-pumping action of respiratory complexes across the inner mitochondrial membrane and couples substrate oxidation to ATP generation.
- Transverse tubules
-
(T-tubules). Invaginations in the sarcolemmal membrane that insert between myofibrils. T-tubules tightly associate with two terminal cisternae (calcium-releasing regions) of the sarcoplasmic reticulum, forming the ‘triads’, which are essential for excitation–contraction coupling.
- Voluntary force production
-
The conscious or ‘voluntary’ production of muscle force (in other words, not triggered by exogenous electrical stimulation).
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Smith, J.A.B., Murach, K.A., Dyar, K.A. et al. Exercise metabolism and adaptation in skeletal muscle. Nat Rev Mol Cell Biol 24, 607–632 (2023). https://doi.org/10.1038/s41580-023-00606-x
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DOI: https://doi.org/10.1038/s41580-023-00606-x
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