SnapShot: Exercise Metabolism

SnapShot: XXXXXXXXXXXXXXXX
Brendan Egan,1 John A. Hawley,2 and Juleen R. Zierath3
1
School of Health and Human Performance, Dublin City University, Glasnevin, Dublin 9, Ireland
AUTHOR
2
Mary XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
MacKillop Institute for Health Research, Centre for Exercise and Nutrition,
AFFILIATION
AustralianXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
Catholic University, Melbourne, VIC 3000, Australia
3
Department of Molecular Medicine and Surgery and Department of Physiology and Pharmacology,
Section of Integrative Physiology, Karolinska Institutet, 17177 Stockholm, Sweden

Sources of energy provision in skeletal muscle Inter-organ communication

ATP hydrolysis ATP + H 2O ADP + P i + H + + energy
Secreted factors: IL-6, IL-15, myostatin,
ATP resynthesis Muscle BAIBA, lactate, exosomes, and others
Anaerobic pathways:
Phosphocreatine degradation ADP + PCr + H + ATP + Cr
Adenylate kinase reaction 2ADP ATP + AMP Adipocytes Bone
Anaerobic glycolysis Glycogen + 3 ADP 2 lactate + 2 H + + 3 ATP

Aerobic pathways:
Carbohydrate oxidation Glucose + 6 O 2 + 38 ADP + 38 P i 6CO 2 + 6H 2O + 38 ATP
Lipid oxidation Palmitate + 23 O 2 + 130 ADP + 130 P i 16 CO 2 + 146 H 2O + 130 ATP Liver Brain

Contraction-induced modulators of gene expression in skeletal muscle

Stimulus Sensor Downstream effector
P iO 2 PHDs HIF-1α
NAD +:NADH SIRTs PGC-1α, FOXO1, p53
AMP:ATP AMPK HDAC, PGC-1α, CREB, SIRT1, HIF-1α
Mechanical stress MAPKs PGC-1α, CREB, ATF2
[Ca 2+] i CaMKs HDAC, CREB, SRF
Mechanosensation FAK mTOR, p70 S6K
Sarcolemmal disruption PA Akt, mTOR, FOXO1

Exosomes CAPILLARY
Glucose FFA

GLUT4 CD36
Autocrine/paracrine
signaling
ATP-PCr
ATP Glucose Glycogen IMTG
FFA
ADP HK PHOS GS FABP Lipolysis
FFA
PA FAK p38, ERK1/2, JNK CaMKII AMPK SIRTs PHDs LDH G-6-P G-1-P
LAC Glycolysis FA-CoA

Akt NAD + NADH

P ATP CPT1
HDAC HDAC RIP140 PYR
ADP
mTOR FOXOs
MurF PGC-1α PGC-1α
TORC1 TORC2 ATP PDH
MAFbx MEF2 CREB GEF ERRα FOXO1 PPARs
V H+
Atrogenes Glucose metabolism Lipid metabolism
IV H + Electron Ac-CoA β-oxidation
transport
MRFs PGC-1α HIF-1β PRC III H + chain
PGC-1β
p70 S6K 4E-BP1 ATP
MyoD MyoG ERRα HIF-1α PGC-1α
II NADH, FADH 2,
Protein MEF2 VEGF ERRα
PPARs NRF-1/2 ATP, CO 2
translation H+ TCA
initiation
Myogenesis Angiogenesis
I cycle
Transcriptional regulators NAD +, FAD,
and mitochondrial genes ADP+P i
mtDNA
miR-1, -133a, -133b, -181a, miR-9, -23a, -23b, -31 NUCLEUS
Tfam
Autophagy MITOCHONDRION

SARCOPLASM

Adaptive Changes in mRNA expression and protein content Hypertrophy

responses:

Change mRNA
from
baseline Protein content, enzyme function Mitochondrial biogenesis
Improved exercise performance
and whole-body metabolism

Acute exercise Hours Days Weeks Months Chronic exercise training

See online version for

342  Cell Metabolism 24, August 9, 2016 © 2016 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cmet.2016.07.013 legend and references
SnapShot: Exercise Metabolism
Brendan Egan,1 John A. Hawley,2 and Juleen R. Zierath3
1
School of Health and Human Performance, Dublin City University, Glasnevin, Dublin 9, Ireland
2
Mary MacKillop Institute for Health Research, Centre for Exercise and Nutrition,
Australian Catholic University, Melbourne, VIC 3000, Australia
3
Department of Molecular Medicine and Surgery and Department of Physiology and Pharmacology,
Section of Integrative Physiology, Karolinska Institutet, 17177 Stockholm, Sweden

Energy Provision for Skeletal Muscle during Exercise

Locomotion is powered by hydrolysis of adenosine triphosphate (ATP). However, [ATP] in human skeletal muscle is only ~25 mmol/kg dry mass. Accordingly, the metabolic
pathways regulating ATP resynthesis are rapidly activated at the onset of intense exercise through substrate-level phosphorylation via the breakdown of creatine phos-
phate (PCr), and during the conversion of glucose units, derived from intramuscular glycogen, to lactate. Substrate-level phosphorylation occurs in the cytoplasm as part of
glycolysis and in mitochondria as part of the tricarboxylic acid (TCA) cycle and proceeds under aerobic and oxygen-independent conditions. During exercise lasting longer
than several minutes, the mobilization of extramuscular substrates (primarily from liver and adipocytes) supports skeletal muscle metabolism. Metabolic signals activating
energy-producing pathways are classified into three categories: calcium release, metabolites related to the cytoplasmic phosphorylation potential ([ATP]/[ADP] [Pi]), and the
mitochondrial reduction/oxidation (redox) state of nicotinamide adenine dinucleotide (NAD+/NADH).

Inter-organ Communication
Cytokines and other peptides that are produced/released by myofibers and exert an autocrine, paracrine, or endocrine effect are classified as myokines (Pedersen and
Febbraio, 2012). Muscle “communicates” with other organs to confer the beneficial effects of exercise on whole-body health. Organ cross-talk may also be achieved by the
release of microRNAs (miRNAs) packaged in exosomes, for transport into circulation and delivery to other tissues (Safdar et al., 2016; Zierath and Wallberg-Henriksson, 2015).
miRNAs play a role in exercise-mediated mitochondrial adaptation as well as muscle development and hypertrophy (Safdar et al., 2016). Clearly a big challenge for exercise
biologists is to connect distinct signaling cascades to defined metabolic responses and gene expression changes that occur after different types of exercise.

How Does Skeletal Muscle Adapt to Repeated Bouts of Exercise?

The molecular bases of skeletal muscle adaptations to exercise (i.e., increased mitochondrial mass, altered substrate metabolism, enhanced angiogenesis, or myofiber
hypertrophy) are mediated by signaling events, pre- and post-transcriptional processes, regulation of translation, and ultimately the increased abundance and/or maximal
activity of proteins with roles in energy provision (Egan and Zierath, 2013; Hawley et al., 2014). Aerobic (or endurance-based) and resistance (or strength/power-based) activi-
ties represent extremes on the exercise continuum. There are multiple and specific stimuli associated with these divergent exercise modes, with various protein kinases that
respond to these different stimuli, and multiple downstream pathways/targets (Egan and Zierath, 2013). These events occur in a temporal manner, such that kinase activation
and pre-transcriptional regulation occur during exercise and recovery, whereas transcript and protein alterations represent stable changes that ultimately result in functional
improvements in exercise capacity/performance and different athletic phenotypes (Egan and Zierath, 2013; Hawley et al., 2014).

Specificity of Molecular Responses to Acute Exercise Regulates Adaptive Responses

A network of transcription factors and coregulator proteins modify the skeletal muscle phenotype in response to exercise. The transcriptional coactivator PGC-1α acts as a
“master” regulator of mitochondrial biogenesis through recruitment and coregulation of multiple transcription factors that control skeletal muscle gene expression, including
NRF-1, NRF-2, ERRα, and Tfam (Egan and Zierath, 2013; Hawley et al., 2014). Upstream kinases (e.g., AMPK, p38 MAPK) and deacetylases (e.g., SIRT1) that control these
transcriptional regulators are activated by acute exercise, coincident with alterations in protein stability, functional activity, and subcellular localization. Conversely, muscle
hypertrophy is largely driven by exercise- and nutrition-induced increases in protein synthesis (MPS) consequent to the activation of mTOR, ribosomal protein S6K (p70S6K ),
and several downstream targets (Smiles et al., 2016). Mechanosensory regulation of MPS involves phosphatidic acid (PA) and activation of focal adhesion kinase (FAK)
proteins, which both activate MPS through mTOR-dependent and independent mechanisms. Protein degradation is primarily dependent on the activity of the ubiquitin-protea-
some pathway (Sandri, 2008) via muscle-specific E3 ubiquitin ligases, muscle atrophy F-box (atrogin-1/MAFbx) and muscle RING finger 1 (MuRF1), which are key regulators of
proteolysis under catabolic conditions. Nutrition and exercise regulate autophagy-lysosome systems, including mitochondrial autophagy, which constitute important degrada-
tion systems ensuring cell component and metabolic turnover.

Adaptive Responses
An individual exercise bout elicits a rapid, but transient, increase in relative mRNA expression of a given gene during recovery. An elevated rate of post-exercise protein
synthesis results in a modest, same-directional change in protein content of enzymes that support growth and metabolism. Training-induced adaptations in substrate metabo-
lism and exercise performance are due to the cumulative effects of each acute exercise bout. Training-induced changes in protein content or enzyme function lead to skeletal
muscle hypertrophy and mitochondrial biogenesis to support a new functional threshold for strength and/or endurance.

ABBREVIATIONS

4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; Ac-CoA, acetyl-CoA; ADP, adenosine diphosphate; AMP, adenosine monophosphate; AMPK, AMP-acti-
vated protein kinase; BAIBA, b-aminoisobutyric acid; [Ca 2+]I, intracellular calcium concentration; CaMK, Ca 2+/calmodulin-dependent protein kinase; CD36, fatty acid translo-
case; CPT1, carnitine palmitoyltransferase 1; CREB, cyclic AMP response element-binding protein; ERK, extracellular signal-regulated kinase; ERR, estrogen-related receptor;
FA-CoA, fatty acyl CoA; FABP, fatty acid-binding protein; FAD, oxidized form of flavin adenine dinucleotide; FADH2, reduced form of FAD; FOXO, forkhead transcription factor,
O-box subfamily; G-1-P, glucose 1-phosphate; G-6-P, glucose 6-phosphate; GEF, GLUT4 enhancer factor; GLUT4, glucose transporter type 4; GS, glycogen synthase; HDAC,
histone deacetylase; HIF, hypoxia-inducible factor; HK, hexokinase; IL, interleukin; IMTG, intramuscular triglyceride; JNK, c-Jun N-terminal kinase; LAC, lactate; LDH, lactate
dehydrogenase; MAPK, mitogen-activated protein kinase; MEF2, myocyte enhancer factor 2; miR, microRNA; MRF, myogenic regulatory factor; mtDNA, mitochondrial DNA;
mTOR, mechanistic target of rapamycin; MyoD, myogenic differentiation 1; MyoG, myogenin; NAD+, oxidized form of nicotinamide adenine dinucleotide; NADH, reduced form
of NAD; NRF, nuclear respiratory factor; PDH, pyruvate dehydrogenase; PHD, prolyl hydroxylase domain; PHOS, glycogen phosphorylase; PGC-1, PPARg co-activator 1; PiO2,
partial pressure of inspired oxygen; PPAR, peroxisome proliferator-activated receptor; PRC, PGC-1-related coactivator; PYR, pyruvate; RIP140, nuclear receptor-interacting
protein 1; SIRT, sirtuin; SRF, serum response factor; Tfam, mitochondrial transcription factor A; TORC, target of rapamycin complex; VEGF, vascular endothelial growth factor.

REFERENCES

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Safdar, A., Saleem, A., and Tarnopolsky, M.A. (2016). Nat. Rev. Endocrinol. Published online May 27, 2016. 10.1038/nrendo.2016.76.

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342.e1  Cell Metabolism 24, August 9, 2016 © 2016 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cmet.2016.07.013