METABOLISM DURING EXERCISE

Exercise has a powerful action on metabolism, and adaptation of the body to changes induced
by exercise is fundamental to be able to provide the energy required for muscle contraction
and physiological functions of vital tissues. (Moghetti P, 2016)

Depending on the intensity and duration of exercise, different mechanisms are called on to
make energy available, and under homeostatic control, this is guaranteed by rapid and
coordinated changes in the secretion of several hormones. Molecular mechanisms controlling
muscle function and fiber phenotype are related to the specific mode of muscle activation.
Besides the acute changes induced by a single exercise session, regular exercise may induce
chronic adaptations, improving exercise capacity and affecting energy metabolism. Notably,
although acute metabolic effects of exercise are mostly due to insulin-independent effects,
exercise training may improve muscle insulin sensitivity and is considered a key tool in the
prevention and treatment of metabolic disorders.

Supply of energy during Exercise

During exercise, the supply of adenosine triphosphate (ATP) is essential for the energy
dependent processes that underpin ongoing contractile activity. These pathways involve both
substrate-level phosphorylation, without any need foroxygen, and oxidative phosphor ylation
that is critically dependent on oxygen delivery to contracting skeletal muscle by the respiratory
and cardiovascular systems and on the supply of reducing equivalents from the degradation of
carbohydrate, fat, and, to a limited extent, protein fuel stores. (Spriet, 2018) The relative
contribution of these pathways is primarily determined by exercise intensity, but also mod
ulated by training status, preceding diet, age, gender, and environmental conditions. Optimal
substrate availability and utilization before, during, and after exercise is critical for maintaining
exercise performance.

Skeleton Muscles Metaoblic Adaptations during physical activity

The contractile activity during exercise is maintained by the supply of adenosine triphosphate
(ATP) to the myosin, Na+-K+, and sarcoplasmic reticulum Ca+2 .ATPase are essential for
myofilament force production and also the maintenance of sarco lemmal excitability and
sarcoplasmic reticulum Ca+ reuptake and release during excitation contraction coupling.
Because the intramuscular stores of ATP are small (≏5 mmol . kg21wet muscle), sole reliance
on them would only sustain exercise for short periods.

During Submaximal Activity

 During submaximal exercise at a poweroutput (200 W) requiring ≏75% maximal oxygen uptake
(VO2max), with an estimated ATP utilization rate of 0.4 mmol ATP. Kg-1 sec-1, exercise duration
would be 15 sec. During submaximal exercise, the oxidative metabolism of carbohydrates and
lipids provides almost all of the ATP required for contractile activity (van Loon LJC, 2001). The
major substrates for oxidation are muscle glycogen and blood glucose derived from liver
glycogenolysis and gluconeogenesis and the gut when carbohydrate is ingested, and FAs
derived from both adipose tissue and intra muscular triglyceride (IMTG) breakdown. The
relative activity contribution of these substrates is largely determined by exercise intensity
(RomijnJA, 1993).And also determined by duration,but is also influenced by training status,
gender, preceding diet, and environmental conditions.

At lower intensities lipid oxidation dominates, but with increasing exercise intensity there is

both extra and intramuscular FAs, occur at ≏60%–65% VO2max,declining at higher intensities
greater reliance on muscle glycogen and blood glucose. Maximal rates of fat oxidation, from

as a result of reduced plasma FA delivery to contracting skeletal muscle and lower rates of
mitochondrial FA up take and oxidation,secondary to increased glycolytic flux (LL,
2014).Increased muscle glycogenolysis at higher exercise intensities is the result of enhanced
glycogen phosphorylase activity, secondary to elevated sarcoplasmic Ca2+, Pi, and cyclic AMP
following adrenaline stimulation and allosteric activation by ATP breakdown (Howlett RA,
1998).

Glucose uptake also in creases in relation to exercise intensity, although glucose utilization may
decrease during intense exercise because of high rates of muscle glycogenolysis and glucose-6-
phosphate-mediated inhibition of hexokinase (Katz A, 1986). The increase in skeletal muscle
glucose uptake is enhanced liver glucose output, initially from liver glycogenolysis but during
more prolonged exercise from increased rates of gluconeogenesis. Rates of carbohydrate
oxidation are increased with increasing exercise intensity in parallel, with PDH activation.

Despite the increased PDH activity, accelerated rates of glycolysis also result in production of
lactate that accumulates in muscle and blood (Spriet LL, 2000) . Although lactate is often
considered simply a metabolic by-product, it is an important substrate for oxidative metabolism
and gluconeogenesis, thereby providing a link between glycolytic and oxidative metabolism
(GA, 2009)

During Maximal: All out Exercise

During maximal, “all out” exercise, with a peak power output of ≏900W, which declines over

majority of ATP, while oxidative phosphorylation accounts for ≏25%–30% of energy

the next 30 sec, the degradation of creatine phosphate and of glycogen to lactate provide the

turnover .The rapid increase in muscle glycogen olysis is the result of activation of glycogen
phos phorylase by increased sarcoplasmic[Ca2+]and inorganic phosphate (Pi), elevated cyclic
AMP secondary to increased circulating adrenaline, and allosteric activation by ATP breakdown
products (AMP, ADP, and IMP). The increase in Ca2+, along with elevated muscle pyruvate
levels caused by increased glycolysis, activates pyruvate dehydrogenase (PDH), the rate-limiting
enzyme for muscle carbohydrate oxidation (Parolin ML, 1999). Despite the increased PDH
activity, the rate of pyruvate production from glycolysis is higher than PDH activity, resulting in
significant generation of lactate that accumu lates in both the muscle and blood. The marked
increases in ATP utilization, glycolysis, and strong ion fluxes during such exercise result in
metabolic acidosis.

Fatigue
The decline in power output (fatigue) during single and repeated bouts of maximal exercise is
associated with creatine phosphate and glycogen depletion (Casey A, 1996), accumulation of
metabolic by-products (e.g., H+, ADP, AMP, Pi) (Hargreaves M, 1998) and hyperkalemia (Medbø
JI, 1990), which singly and in combination impact on excitation–contraction coupling processes
within skeletal muscle (Allen DG, 2008).

During strenuous activity

During prolonged, strenuous (≏75% VO2max) exercise, there is a progressive decline in the rate
of muscle glycogenolysis and lipolysis, increased muscle glucose uptake, and a progressive
increase in FA oxidation with elevated plasma FA levels (Omijn JA, 1993) with increasing
exercise duration. Fatigue during such exercise is often associated with muscle and liver
glycogen depletion and hypoglycemia, with a consequent decrease in muscle carbohydrate
oxidation and neuroglucopenia. Increased dietary carbohydrate intake to maximize pre-exercise
carbohydrate stores (Hawley JA, 1997) and carbohydrate ingestion during exercis (Cermak NM,
2013) are effective nutritional strategies to enhance endurance exercise performance.
Above Figure: Schematic overview of skeletal muscle metabolism. Hb, Hemoglobin; FFA, free
fattyacid; FABPpm andFABPc, fattyacid binding protein–plasma membrane and cytoplasm;
FAT/CD36, fatty acid trans locase; FATP, fatty acid transport protein; GLUT1 and 4, glucose
transport proteins 1 and 4; PM, plasma membrane; ATG, HS, and MG lipases, adipocyte
glyceride, hormone-sensitive, and monoglyceride lipases; mtOMand mtIM, outer and inner
mitochondrial membranes; CPT-I and-II, carnitine palmitoyl transferase I and II; ACT,
acylcarnitine transferase; G-1-P and G-6-P, glucose 1 and 6 phosphate; HK, hexokinase; PFK,
phosphofructokinase; LDH, lactate dehydrogenase, MCT, monocarboxylate transport proteins;
PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid; ANT, adenine nucleotide transport
protein; Cr and PCr, creatine and phoshocreatine; CK and mtCK, creatine kinase and
mitochondrial CK

HOW EXERCISE-INDUCED MUSCLE GLUCOSE UPTAKE AND GLUT4

TRANSLOCATION
Muscle glycogen is important as a carbohydrate fuel source for contracting skeletal muscle
during exercise, blood glucose nevertheless makes an important contribution to overall
carbohydrate oxi- dation, especially during prolonged, strenuous exercise.

The regulation of skeletal muscle glucose up take during exercise is very important and
interesting because this glucose uptake is preserved in states of insulin resistance such as type
2 diabetes (Martin IK, 1995),It is well known that the effects of insulin (when increased before
or during exercise) and exercise on skeletal muscle glucose uptake are additive/synergistic but
mediated via different mechanisms. (DeFronzo RA, 1981). Skeletal muscle glucose uptake
occurs by facilitated diffusion and there are three sites of regulation: (1) glucose delivery, (2)
sarcolemmal glucose transport, mediated by the GLUT4 glucose transporter, and (3) glucose
phosphorylation by hexokinase and subsequent metabolism (Wasserman DH, 2011). Glucose
transport is thought to be rate-limiting under resting con- ditions, the large increases in glucose
delivery, secondary to skeletal muscle hyperemia, and glucose transport caused by rapid GLUT4
translocation to surface membranesmean that glucose phosphorylation becomes an important
site of regulation during exercise. (Kristiansen S, 1997).

During intense exercise and the early stages of prolonged exercise when rates of muscle
glycogenolysis are at their highest. That said, glucose delivery remains an important
determinant of muscle glucose uptake during exercise (Zinker BA, 1993). GLUT4 is essential for
exercise-induced muscle glucose up take (Howlett KF, 2013). Investigators have used numerous
in vitro, in situ, and in vivo ex perimental models invarious species, a range of pharmacological
inhibitors of critical enzymes, and transgenic and knockout models. Muscle
contraction/exercise is a complex stimulus that generates multiple signals, including increased
sarcoplasmic [Ca2+], mechanical stress/force, metabolic perturbations (increased AMP/ATP and
decreased creatine phosphate and glyco gen), changes in redox state associated with in creased
levels of reactive oxygen species (ROS) and increased nitric oxide (NO). In turn, such signals
activate various signaling pathways and protein kinases, notably Ca2+/calmodulin-pendent
protein kinase (CaMK), protein kinase C (PKC), and AMP-activated protein kinase (AMPK). These
kinases act on downstream tar gets, notably TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family
member 1) and AS160 (Akt substrate of 160 kDa or TBC1 domain family member 4—TBC1D4)
that are involved in the regulation of GLUT4 vesicle trafficking.The fundamental importance of
Ca+2 in muscle contraction, there is that it stimulates glucose transport. A recent study has
suggested that calcium effects, in the absence of force genera tion, are mediated via activation
of energy-de pendent processes within muscle that, in turn, increase AMPK activity and glucose
transport (Jensen TE, 2014).

AMPK activation and mechanical stress, not sarcoplasmic Ca2þ release, were the primary
mediators of contraction-stimulated glucose uptake. Another calcium-sensitive ki nase is PKC;
however, knockout of PKCa, the major isoform in skeletal muscle, did not have any effect on
contraction-stimulated glucose uptake (Jensen TE M. S., 2009). AMPK is an important energy-
sensing kinase expressed in skeletal muscle that is acti vated by exercise in an intensity-
dependent manner (Friedrichsen M, 2013). Other factors involved in the stimulation of glucose
uptake during contractions/exercise in clude ROS and NO (Merry TL, 2010).

Important downstream targets of the above-mentionedsignalingcascadesaretheRab GTPase-

activatingproteinsTBC1D1andAS160 that are involved in the interactions between Rab proteins
and GLUT4 vesicles during the various events required for translocation of GLUT4 from
intracellular sites to the surface membranes. Because insulin and muscle contractions/exercise
result in distinct and different phosphorylation signatures of both these proteins (GD, 2015). It
has been suggested that these proteins may be important sites of convergence of the insulin
and contraction/ex ercise signaling pathways, thereby accounting for the additive effects of
these two stimuli and potentially contributing to enhanced mus cle insulin sensitivity in the
postexercise period (GD, 5. Roles of TBC1D1 and TBC1D4 in insulin and exercise-stimulated
glucose transport of skeletal muscle, 2015).

Awell-known adaptation to exercise train ing is a reduction in carbohydrate oxidation during

exercise associated with reduced glucose turnover and oxidation, at least at the same absolute
power output (Coggan AR, 1990). At maximal exercise in tensities, there may be an increase in
muscle glucose uptake associated with an increased ca pacity for glucose transport caused by
increased muscle GLUT4 protein expression following training This increase in
GLUT4expressionisalsoanimportantfactor underlying enhanced muscle insulin sensitivity and
muscle glycogen storage in the trained state. The molecular mechanisms responsible for the
increase in muscle GLUT4 expression following exercise training include many of the pathways
responsible for the increases in glucose trans port with acute exercise (Richter EA, 2013).

SKELETAL MUSCLE FATTY ACID OXIDATION

The regulation of fat metabolism in skeletal muscle during exercise lags behind that of
carbohydrate metabolism but many sites of control are similar in location to that of
carbohydrate, including the protein-mediated transport of fat into muscle and the degradation
of stored IMTG (LL., 2012). However, other control sites are unique to fat metabolism, in
cluding the binding of fat to a protein chaper one and transport in the cytoplasm, and the
protein-mediated transport of fat into the mi tochondria (Campbell, 2004).

Other recent discoveries include the identification of the enzyme adipose tissue glyceride lipase
(ATGL) that works in concert with hor mone-sensitive lipase (HSL) to regulate skeletal muscle
lipolysis (Zimmermann R, 2004).The presence of perilipin like proteins coating the lipid droplets
in skel etal muscle is also found to be in regulation of muscle lipolysis (MacPherson RE, 2015).
Another possible site of regulation that has not been explored is control within the beta-
oxidation pathway and mitochondria volume determines the overall capacity to oxidize fat
(Holloway GP, 2009).

HOW EXERCISE-INDUCED MUSCLE FATTYACID UPTAKE AND FAT TRANSPORT

PROTEIN TRANSLOCATION
Although a small amount of fat can diffuse through the lipid bilayer of the muscle mem brane
into the muscle cell, it is now widely accepted that the major portion of the FAs that enter
muscle do so via protein-mediated mechanisms (Glatz JF, 2010). This involves actual transport
of FA across the muscle membrane by carrier proteins and facilitation of their movement across
the membrane by initial binding to transport proteins. The major trans port proteins include the
plasma membrane fatty acid–binding protein (FABPpm) located on the outer leaflet of the
plasma membrane a family of fatty acid transport proteins (mainly FATP1, 4) that have many
transmembrane domains, and, most importantly, the fatty acid translocase (FAT/CD36) protein
that has two transmembrane domains. Much of the pioneering research was performed in red
and white rodent skeletal muscle in which the in vestigators showed a strong relationship
between the expression and protein content of the putative transporters and actual FA uptake.
The messenger RNA (mRNA) abundance and protein content of the FA transporters in the
plasma membrane and the FA transport capacity were several fold higher in red oxidative
rodent muscle (high capacity for fat metabolism) versus white glycolytic muscle (Bonen A,
1998).
FAT/CD36 acute ly translocated from an intracellular pool to the muscle membrane in rodent
and human skele tal muscle during a single bout of muscle con tractions, very similar to GLUT4
(Bradley NS, 2012). The muscle contractions also increased the plasma membrane content of
FABPpm, FATP1 and 4 proteins in mouse skeletal muscle and that the membrane content of
FAT/CD36, FABPpm, and FATP4 but not FATP1 correlated highly with the capacities for
oxidative metabolism and FA oxidation in six different rat skeletal muscles.

The movement of fat into skeletal muscle during exercise is ahighly regulated process
involving sev eral transport proteins that are responsive to both the acute and chronic need for
fat as a fuel source. However, there has been less work to clarify the factors that activate the
translocation of fat transporter proteins to the muscle membrane during exercise. It is expected
that Ca2þ andthefactors related to the energystatus of the cell (e.g., free ADP, Pi, and AMPK
activa tion) would be involved as they play an impor tant role in activating the transport and
docking of GLUT4 into the muscle membrane. In skeletal muscle, contraction and the activa tion
of muscle AMPK by the pharmacological activator 5-aminoimidazole-4-carboxamide-1 b-D-
ribofuranoside(AICAR) produced translocation of both GLUT4 and FAT/CD36 to the sarcolemma
(Jain SS, 2009).

TRANSCRIPTION FACTORS ROLE IN METABOLISM DURING EXERCISE

Endurance exercise improves insulin sensitivity and increases fat oxidation, which are partly
facilitated by the induction of metabolic transcription factors. Next to exercise, increased levels
of FFA’s also increase the gene expression of transcription factors, hence making it difficult to
discern the effects from contractile signals produced during exercise, from those produced by
increased circulatory FFA’s. In human skeletal muscle, whether acute exercise affects gene
expression of metabolic transcriptional co-activators and transcription factors, including PGC-
1α, PRC, PPARα, β/δ, and γ and RXR, SREBP-1c and FKHR, and to discern the effect of exercise
per se from those of elevated levels of FFA. The regulation of metabolic genes involved in
improved insulin sensitivity and increased fat oxidation is under the control of several
transcriptional co-activators and transcription factors, which are also regulated by exercise and
include peroxisome-proliferator-activated receptor (PPAR)-γ co-activator-1 (PGC-1α) the PPAR
family, sterol regulatory element binding protein-1c (SREBP-1c) , and the forkhead type
transcription factor, FKHR (also known as Foxo1) (Kamei, 2003).

PGC-1α is a nuclear transcriptional co-activator that regulates several important metabolic

processes, including mitochondrial biogenesis, adaptive thermogenesis, respiration, insulin
secretion, and gluconeogenesis. The expression of PGC-1α mRNA is prominent in tissues with
high-energy demands, such as heart and skeletal muscle as the nuclear respiratory factors 1
and 2a (NRF-1 and NRF-2a) (Wu, 1999).

A new member of the PGC-1 family, PGC-1-related co-activator (PRC) contains several domains
homologous to PGC-1α, which are important for interacting with both nuclear receptors and
RNA. Functional studies have shown that PRC directly co-activates NRF-1 and when cooperating
with CBER coactivates cytochrome-c. RC has functional implications similar to PGC-1α, and its
potential coactivation of transcription factors would result in increases in genes regulating
mitochondrial biogenesis and oxidative phosphorylation.

A network of target genes involved in substrate metabolism is under the control of the nuclear
receptor superfamily of PPARs. The three PPAR isoforms known so far (PPARα, PPARβ/δ and
PPARγ) are functionally incongruent (Evans, 2004) For example PPARα and PPARγ jointly
regulate plasma lipid profiles by induction of fatty acid oxidation on the one hand (PPARα) and
lipogenesis and lipid storage in liver and adipose tissue on the other (PPARγ). In addition, PPARγ
has been implicated in the regulation of whole body insulin sensitivity. Hence, PPARα and γ are
targets in the treatment of hyperlipidemia and insulin resistance, both of which can also be
improved, probably along the same lines, by endurance exercise. On the other hand, activation
of PPARβ/δ induces genes involved in lipid catabolism and adaptive thermogenesis. The
thermogenic role of PPARβ/δ closely mimics the effect of PGC-1α. (Puigserver, 1998).

SREBP-1c plays a crucial role in regulating genes involved in directing fatty acids towards
storage and has been suggested to up-regulate fatty acid synthase (FAS), acetyl-CoA
carboxylase-1 (ACC-1), and stearoyl-CoA desaturase-1 (SCD-1). (Ikeda, 2002). FKHR has been
suggested to influence glucose oxidation by regulating glucose –6-phosphatase pyruvate
dehydrogenase-4 (PDK4) and lipoprotein lipase (Schmoll, 2000) (Furuyama, 2003).

Signaling molecules, including free fatty acids (FA), circulating hormones and glycogen, are
known to regulate gene transcription. Fasting, a condition that rapidly increases the levels of
circulating FFA’s has been shown to increase the gene expression of liver PGC-1α mRNA (Herzig,
2003), while it is well known that fatty acids regulate the PPAR family. In contrast it has been
shown that FA’s down-regulate SREBP activity.As physical exercise stimulates lipolysis and
increases circulatory FFA levels, the effect of exercise, per se, on induction of metabolic
transcription factors can be biased by elevated FFA levels. In an attempt to better understand
the pathways involved in eliciting the adaptive response to exercise, the aim of the present
study was to investigate the effect of acute endurance exercise on the mRNA regulation of the
above mentioned key metabolic transcriptional co-activators and transcription factors and to
delineate the effect of exercise from the effect of elevated levels of circulating FFA. To this end,
exercise was performed once in the fasted state and once in the glucose-fed state.
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