Download Hypoxia in skeletal muscles: from physiology to gene expression

Musculoskeletal Regeneration 2016; 2: e1193. doi: 10.14800/mr.1193; © 2016 by Zhuohui Gan
http://www.smartscitech.com/index.php/mr
REVIEW
Hypoxia in skeletal muscles: from physiology to gene
expression
Zhuohui Gan
Department of Bioengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0412, USA
Correspondence: Zhuohui Gan
E-mail: [email protected]
Received: January 16, 2016
Published online: February 29, 2016
Hypoxia is studied as a common clinical factor and a condition associated with a number of diseases. The
responses induced by hypoxia in tissue are hypoxia severity and duration dependent. Compared with other
tissues, skeletal muscles are relatively tolerant to hypoxia due to its low oxygen demand and its adaptation to
hypoxia during physical exercise. This review focuses on molecular responses of skeletal muscles to hypoxia,
with an emphasis on signaling pathway. Based on published works, hypoxia in skeletal muscle induces a number
of responses involving energy metabolism, redox metabolism and angiogenesis. Signaling pathways including
PI3K/Akt signaling, AMPK/mTOR signaling, HIF signaling as well as Notch signaling are widely involved in
these responses. Energy metabolism associated signaling pathways such as PI3K/Akt signaling, AMPK/mTOR
signaling are active during hypoxia in skeletal muscles.
Keywords: hypoxia; skeletal muscle; mitochondria; metabolism; signaling pathway; angiogenesis; PI3K/Akt signaling
To cite this article: Zhuohui Gan. Hypoxia in skeletal muscles: from physiology to gene expression. Musculoskelet Regen
2016; 2: e1193. doi: 10.14800/mr.1193.
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Introduction
Hypoxia is identified as a clinical factor widely associated
with a number of pathological, physiological or
environmental conditions. Diseases such as anemias, shock,
acute respiratory distress syndrome can induce a whole body
or tissue hypoxia due to the insufficient oxygen availability
under these pathophysiological conditions [1-4]. Hypoxia is
also identified as an important clinical factor in tumor
metastasis as well as a role involved in normal tissue
development and differentiation [5-7]. Additionally, exposure
to high altitude is an environmental condition which induces
a whole body hypoxia due to the decreased barometric
pressure and hence a decrease in arterial oxygen pressure [8, 9].
Another situation that potentially results in hypoxia is
physical exercise, where the exercising skeletal muscle
undergoes oxygen tension due to the rapid oxygen
consumption [10-12]. Therefore, hypoxia is widely studied as a
common clinical factor and a condition widely associated
with lethal diseases.
It is worth noticing that responses to hypoxia are
dependent on the severity and duration of hypoxia. For
example, insulin resistance is widely reported accompanying
hypoxic exposure. Baum et al. observed insulin resistance in
dogs exposed to 8% O2 for 30 minutes but not dogs exposed
to 10% or 12% O2 for 30 minutes [13]. Similarly, the
decreased blood glucose is observed in subjects exposed to 8%
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O2 for 15-30 minutes but not 12% O2 [14]. These differential
responses suggest a dependency of hypoxia responses on
hypoxia level. On the other hand, the hypoxic duration also
affects hypoxia responses. For example, the insulin
resistance which can’t be observed in 30 minutes of exposure
to 10% O2 is observed in 24 hours of exposure to 10% O2 [15].
Longer exposure such as 4 weeks exposure to 10% O2 can
then lead to an increase in insulin sensitivity [15]. Similarly,
the changes on blood glucose also indicate a temporal feature.
The glucose level decreases in 2 hours of exposure to 11%
O2 and then recovers to the normal level after 4 hours of
exposure [16]. Though changes on gene expression under
hypoxia, especially in the early stage of hypoxia, are poorly
studied, the existing studies suggest a similar dynamic
feature. For example, the expression of glucose transporter 4
(GLUT4) is increased after mice one-day exposed to 10% O2
and recovers to the normal level after 4 weeks of exposure.
[15]
. In summary, hypoxia responses show a dynamic feature
which is hypoxic-duration and hypoxic-severity dependent.
Compared with other tissues such as brain, heart, which
are oxygen-sensitive, skeletal muscles are relatively tolerant
to hypoxia, probably due to the energy buffering system, the
relatively less demand of oxygen and its accustom to hypoxia
during physical exercise [17-19]. However, hypoxia still
induces a number of responses in skeletal muscles. Chronic
hypoxia reduces fiber area to improve oxygen diffusion into
muscle cells and muscle mass to decrease oxygen demand,
along with a developed muscle fiber atrophy due to the
inhibition of protein synthesis caused by energy stress under
hypoxia [20]. Acute hypoxia induced by exercise can lead to
skeletal muscle vasodilation and hence maintain the delivery
of O2 as a compensatory response [21]. As a metabolically
active tissue, a rapid switch from aerobic to anaerobic
metabolism is observed in skeletal muscles during hypoxic
exposure [22-24]. Hypoxia studies of skeletal muscles also
report impairments of mitochondrial functions and increased
production of reactive oxygen species [19, 23, 25-27]. Recent
studies suggest that these responses are associated with
signaling pathways such as 5'-AMP-activated protein kinase /
mammalian target of rapamycin (AMPK/mTOR) signaling,
hypoxia
inducible
factor
(HIF)
signaling
and
phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)
signaling [28-32]. To further our understanding of the effects of
hypoxia on skeletal muscles, this review briefly summaries
the changes on biological systems including redox
metabolism, energy metabolism and angiogenesis in skeletal
muscles under hypoxia and the involved signaling pathways
in these changes.
The effects of hypoxia on biological systems in skeletal
muscles
I. Changes in mitochondria and redox metabolism during
hypoxia
It is well-known that hyperoxia induces oxidative stress,
while hypoxia is also demonstrated as a trigger of oxidative
stress due to the increase in the generation of reactive oxygen
species (ROS) [33-35]. Mitochondria is the most important
source of ROS due to the leakage of electron in the
respiratory chain at complex I and complex III [36]. The
impairment of mitochondrial respiratory chain increases
electron leakage and hence results in an increase in
mitochondrial production of reactive oxygen species (ROS)
[37, 38]
. A decrease in mitochondrial density and an
impairment of the activity and coupling of mitochondrial
respiratory chain, accompanying with an increased
production of mitochondrial ROS, are observed in skeletal
muscles in chronic obstructive pulmonary disease (COPD)
patients who suffer from chronic hypoxia [36]. Consistently,
Magalhaes et al. report a functional impairment of
mitochondrial complex V in skeletal muscles during an acute
hypoxia induced by eccentric exercise [12]. A switch of
mitochondrial complex IV subunits COX4-1 and COX4-2 is
discovered by Fukuda et al. which contributes to the change
of complex IV activity under chronic hypoxia [39]. Similarly,
a decrease in oxygen consumption through mitochondrial
state III respiratory in skeletal muscles from rats exposed to
high altitude for 30 days is found [40]. These results suggest
an impairment of mitochondrial function along with an
increase in ROS in skeletal muscles exposed to either chronic
or acute hypoxia. In Horscroft et al.’s review regarding
hypoxia-induced changes in skeletal muscles, he points out
that mass-specific mitochondrial function is decreased prior
to mass-specific mitochondrial density, implicating
intra-mitochondrial changes in the response to environmental
hypoxia. [23]. Recently, Jacobs et al. reported an increase in
the mitochondrial volume density in skeletal muscle after 28
days of exposure to high altitude [41], where the
mitochondrial function is not affected through either
complex I or complex II [42] . This result partially agrees with
Horscroft’s conclusion. Along with the changes on
mitochondria, the production of nitric oxide (NO) is
increased quickly either in oxygen sensitive tissue such as
brain or oxygen tolerant tissue such as skeletal muscle during
ischemia [43, 44]. As a vasodilator, the increase of NO
production plays a role in vasodilation. Joyner et al. suggests
that NO played the role by linking to a β-adrenergic receptor
mechanism in hypoxia caused by a low intensity exercise [21].
Though the synthesis of NO is increased in the acute hypoxia,
the hypoxia study in smooth muscle by McQuillan et al.
suggests a decrease in mRNA transcription of endothelial
NO synthase (eNOS) following a decrease in eNOS mRNA
half-life after 24 hours of hypoxia [45]. This inconsistence
suggests the complexity of the relationship between mRNA
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expression and protein synthesis. Studies in brain suggest the
potential role of NO on the activation of p38
mitogen-activated protein kinase (MAPK), extracellular
signal-regulated kinase (ERK) and c-jun N-terminal kinase
(JNK) under hypoxia [46]. Besides NO, increases in the
activity of anti-oxidant enzymes such as superoxide
dismutase (SOD) which removes superoxide and catalase
(CAT) which removes hydrogen peroxide as well as
pro-oxidant enzymes such as NADPH oxidase are also
reported [47]. Thus, the redox system is active under hypoxia
as both the pro-oxidants and the anti-oxidants are responded.
II. Changes in energy metabolism during hypoxia
Due to the shortage of O2 supply, ATP production through
oxidative phosphorylation in mitochondria is decreased
during hypoxia [48]. A rapid switch from aerobic to anaerobic
metabolism such as glycolysis is observed during hypoxic
exposure [22-24, 49]. The expression of glucose transporters
such as GLUT1 and GLUT3, glycolytic enzymes and lactate
dehydrogenase are increased [23, 48, 50]. It is believed that the
changes of blood glucose due to the inhibition of oxidative
phosphorylation cause the up-regulation of GLUT-mediated
glucose transport [51]. Briefly, more GLUTs are translocated
to plasma membrane and transporters pre-exiting in the
plasma membrane are activated [51], while prolonged
exposure to hypoxia suggest an enhancement of transcription
of GLUT1 and GLUT4 [16, 51, 52]. These responses contribute
to the optimization of the ATP synthesis in the face of the
down-regulated oxidative metabolism under the hypoxic
environment. Hypoxia inducible factor (HIF-1) is suggested
as a primary regulator of the stimulated expression of GLUT
and glycolytic enzymes under hypoxia [53-55]. Blood insulin,
which is highly relevant to blood glucose [14], is increased its
level and decreased its sensitivity in skeletal muscles under
hypoxia [56]. Published works indicate a relationship between
insulin resistance and a decrease in Akt activity in PI3K
signaling pathway [56-59]. Besides glycolysis, the increased
pyruvate dehydrogenase kinase is considered as another way
to compensate the decreased ATP production [55]. This
response might be tissue specific since, in cardiac muscles, a
decrease in pyruvate metabolism is reported [17]. Furthermore,
Norrbom et al. report an enhancement of fatty acid
metabolism in skeletal muscles during acute hypoxia induced
by exercise [60], while Morash et al. report a reduction of
fatty acid oxidation in skeletal muscle during hypoxia [17].
These results suggest a potential role of fatty acid
metabolism in energy rebalance during hypoxia.
III．Changes in angiogenesis during hypoxia
A number of studies have indicated that hypoxia is a
trigger of angiogenesis [28, 61-63]. In brain, significant increase
in angiogenesis is found after mice exposed to moderate
hypoxia for 3 weeks [64]. Though Lundby et al. suggest that
hypoxia does not appear to promote angiogenesis in skeletal
muscles at rest [4], skeletal muscles exhibit the capacity to
generate new capillaries as an adaptation to exercise training
[65]
. Angiogenesis associated with hypoxia is suggested as a
complex process that has been tested in both in vitro and in
vivo studies [61]. HIF-1 is found as an important regulator
which affects angiogenesis in several ways including
angiogenic factors, proangiogenic chemokines and their
receptors, leading to neovascularization and protection
against hypoxic injury [66-68]. Among those angiogenic factors,
vascular endothelial growth factor (VEGF) is known as the
most prominent proangiogenic factor that can be activated by
[69,
70]
hypoxia
.
Recent
studies
suggest
peroxisome-proliferator-activated receptor-c coactivator-1α
(PGC-1α) as an independent regulator of VEGF expression,
angiogenesis in cultured muscle cells and angiogenesis in in
vivo skeletal muscle [62]. Besides VEGF, the strong increase
of Erythropoietin (EPO), which is required for the formation
of red blood cells, can be another contributor for the
angiogenesis during hypoxia [71]. Additionally, hypoxia has
been shown to increase the rate of collagen synthesis.
Exposure of mice to hypoxia induced up-regulation of
collagen type I and type III expression [72]. Transcriptional
studies indicate that a number of genes involved in
angiogenesis have been shown to increase by hypoxia [73].
For example, Myllyharju et al. shows an increase in mRNA
expression of proteins in collagen chains such as Proα1(I),
proα1(III), and α2(IV) and vertebrate collagen P4Hs I and II
after hypoxic exposure [1]. LOX which are likely involved in
extracellular matrix synthesis are also strongly increased its
gene expression during hypoxia [74, 75].
The role of signaling pathways in hypoxia responses
I. AMPK/mTOR signaling
AMPK is an important energy sensor. Stimuli either
inhibiting ATP synthesis or accelerating ATP consumption
can activate AMPK, including hypoxia which induces an
energy stress [76, 77]. The activation of AMPK can repress
fatty acid synthesis while enhance fatty acid uptake, fatty
acid oxidation and glucose uptake [76, 78, 79]. In skeletal
muscles, changes induced by AMPK activation can be acute
through the direct phosphorylation of metabolic enzymes, or
chronic, through the control of gene expression [30]. In our
transcriptomic study on hours of hypoxia in mouse skeletal
muscles (results not published yet), the gene changes are
enriched in AMPK/mTOR signaling pathway, suggesting the
involvement of AMPK/mTOR signaling in gene responses.
Peroxisome proliferator-activated receptor α (PPARα) is
critical for muscle endurance since it is an important
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regulator of fatty acid oxidation. In skeletal muscles, a
decrease in PPARα expression is found during hypoxia [17].
Li et al. suggests that the hypoxia-induced increase in
PPARα was AMPK dependent [80]. Additionally, PGC-1α,
the co-activator of PPARα and the master regulator of
mitochondrial biogenesis, has been shown an increased gene
expression induced by the activation of AMPK in skeletal
muscle [27]. The AMPK-dependent phosphorylation of
PGC-1α initiates gene regulatory functions of AMPK in
skeletal muscles including the expression of glucose
transporter 4 (GLUT4), mitochondrial genes, and PGC-1α
itself [27]. PGC-1α and its co-activator can induce expression
of E2-related factors NRF-1 and NRF-2, which can enhance
the expression of nuclear-encoded subunits of respiratory
chain [81]. Furthermore, they also act on the promoters of
genes encoding transcription factors for mtDNA such as
mitochondrial transcription factor A (TFAM), mitochondrial
transcription factor B1 (TFB1M) and mitochondrial
transcription factor B2 (TFB2M) [82, 83]. Consistently, after
muscle cells exposed to hypoxia for 5 days, a significant
increase in NRF-2α expression and a decrease in TFB2M
expression are observed [27]. Additionally, chronic hypoxia
studies also suggest that the activation of AMPK is essential
for mitochondrial biogenesis in muscle tissue [84, 85]. In
addition to the direct regulation on mitochondrial
bioenergetics and metabolic bioenergetics, Benziane et al.
reported an AMPK-dependent activation of an
energy-consuming
ion
pumping
process,
where
cyanide-induced artificial anoxia induced an activation of
AMPK and hence promoted translocation of the Na+,
K+-ATPase α1-subunit to the plasma membrane in muscle
cells [77]. In summary, as an energy sensor, AMPK plays an
important role in hypoxia responses, where metabolism and
gene expression are widely regulated.
II. Insulin/PI3K signaling
Insulin resistance is widely reported during hypoxia [13, 15,
. This might be relevant to the changes on blood
glucose during hypoxia as the blood insulin is highly relevant
to blood glucose [14]. Previous studies suggest that this
resistance is associated with changes on Akt activity in
PI3K/Akt signaling pathway [57-59]. Hypoxia can inhibit
PI3K/Akt pathway in a predominantly HIF-1α-independent
manner [89]. The deprivation of oxygen affects Akt activity by
reducing insulin-like growth factor I receptor sensitivity to
growth factors and hence contributes to insulin resistance
under hypoxia [89]. D’Hulst et al. further points out that
though insulin resistance is observed in skeletal muscles, the
development of whole body insulin intolerance is not
affected by the defect of insulin signaling in skeletal muscles
[16]
. This suggests that the changes on PI3K/Akt signaling are
not skeletal muscle specific.
16, 52, 86-88]
The changes on PI3K/Akt signaling play a role of hypoxia
responses. Majmunda et al. suggest that Akt could be a key
molecular link between oxygen and skeletal muscle
differentiation [89]. Recently, heme oxygenase 1 (HO-1),
which plays a protective role against insulin resistance, is
found to increase its expression by PI3K/Akt signaling
through an activation of nuclear translocation of NRF-2
during hypoxia [90]. PI3K/Akt signaling is also reported as a
regulator of HIF-1 activation evidenced by the up-regulation
of HIF-1 transcription by PI3K/NF-κb [91] and the repression
of the activation of HIF-1 by targeting PI3K/Akt [92]. In our
transcriptomic study on hours of hypoxia in mouse skeletal
muscles (results not published yet), insulin/PI3K signaling is
identified as an important nodal signaling pathway. These in
vivo studies suggest insulin/PI3K signaling could play a big
role in hypoxia responses.
III. HIF signaling
HIFs, whose protein level is increased by the inhibition of
its degradation when O2 supply is insufficient, play an
important role in hypoxia responses [29]. The discovered
members of HIF family include HIF-1α, HIF-2α and HIF-3α.
HIF-1α is considered as the dominant member, while HIF-3α
negatively regulates HIF-1α and HIF-2α due to the lack of
C-terminal transactivation [93]. Previous studies indicate that
one hour of systemic exposure to 6% O2 is sufficient to
increase HIF-1α protein level in most organs including
skeletal muscles [94]. However, the HIF-1α protein level in
skeletal muscles exposed to altitude (~11-12% O2), either
acutely or chronically, is barely modified [95]. Lundby et al.
summarize published work on altitude hypoxia and conclude
that HIF-1 signaling is only activated to a minor degree by
hypoxia in skeletal muscles [4]. The difference in hypoxic
severity, severe hypoxia (6% O2) vs. moderate hypoxia (~12% O2),
may be a cause of the different conclusions. On the other
hand, at to the gene expression, Slivka reports that exercise
but not one hour of hypobaric hypoxia exposure (~13% O2)
plays a role on gene expression of HIF-1α in skeletal muscles
[96]
. Furthermore, Robach et al. suggests that HIF-1α protein
expression is probably not regulated at the transcriptional
level since high altitude only permanently up-regulates
mRNA level of HIF-1α but not protein level of HIF-1α in
skeletal muscles [97]. In our transcriptomic study on hours of
hypoxia in mouse skeletal muscles, mRNA of HIF-1α and
HIF-2α is not changed in up to 6 hours of severe hypoxic
exposure (8% O2), though the protein level of HIF-1α is
supposed to be increased. This result partially agrees with
above argument.
As an important transcription factor induced by hypoxia,
HIFs regulate a number of genes containing a hypoxia
response element (HRE) in their regulatory sequences.
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Genome-wide chromatin immunoprecipitation assay
identified several hundreds of genes as targets of HIFs [98, 99],
which play roles in the reduction in oxygen consumption,
enhancement of oxygen delivery, regulation of inflammation,
angiogenesis and extracellular matrix homoeostasis in
hypoxic conditions [1]. Lee et al. summarizes that the target
genes of HIF-1α are especially enriched in functions
associated with angiogenesis, cell proliferation/survival, and
glucose/iron metabolism [100]. In our transcriptomic study,
HIF signaling pathway is identified as one of the gene
responses-enriched pathways in skeletal muscles after hours
of systemic hypoxic exposure. These results indicate the role
of HIF signaling pathway in gene regulation in skeletal
muscles during hypoxia.
IV. VEGF signaling
VEGF plays an important role in angiogenesis, which
directly participates in angiogenesis by recruiting endothelial
cells into hypoxic and avascular area and stimulating their
proliferation [101]. Hypoxia stimulates the secretion of VEGF,
which protects against hypoxia injury [102]. HIF-1α plays a
role of the increased VEGF as HIF-1α is identified as a
trigger of the transcription of VEGF [73]. The expression of
VEGF gene is critically important for angiogenesis in
skeletal muscles because the deletion of VEGF gene in the
mouse has been shown to greatly reduce skeletal muscle
capillarity [26]. An increase in the mRNA level of VEGF is
found during hypoxia induced by exercise in skeletal muscles
[103]
. However, in our transcriptomic study when mice are
exposed to acute severe hypoxia, the mRNA level of VEGF
is decreased in skeletal muscles. This suggests that the gene
responses of VEGF could be stimulus-dependent. How the
changes on mRNAs translate into the functional responses is
not clear yet, especially for those temporary changes during
an acute stimulus. Additional mechanisms that can signal
VEGF activation in skeletal muscles during hypoxia include
inflammation, which is possibly linked to oxidative stress, or
an energy stress reflected by AMP kinase activity [26].
V. PGC signaling
PGC-1α, a potent metabolic sensor and regulator, is
reported as a transcriptional co-activator which could be
induced by hypoxia [104]. Shoag’s study shows a powerful
induction of PGC-1α gene expression in muscles during
exercise which does not appear to require HIF activity [104].
This induction of VEGF expression by PGC-1α is also
demonstrated as HIF-independent [104]. However, O’Hagan
finds the PGC-1α dependent induction of HIF target genes is
regulated by HIF-1α protein stabilization but not HIF-1α
mRNA level [105]. Recently, Baresic et al. investigated the
effect of PGC-1α on transcriptional network and suggests
that ERR-α and the activator protein 1 complex (AP-1) play a
major role in regulating the PGC-1α-controlled gene program
of the hypoxia response [106].
Several studies have been done to discover the cause of
PGC-1α induction during hypoxia. Jager et al. suggest that
AMPK phosphorylates PGC-1α directly during hypoxia [76].
Insulin signaling is found to inhibit PGC-1α activity through
Akt [107]. A more recent study indicates that PGC-1α
expresses its truncated forms which confer angiogenic
specificity to the PGC-1α-mediated hypoxia response in
skeletal muscle cells [108].
The role of PGC-1α during hypoxia is widely studied.
PGC-1α transcriptionally activates the nuclear respiratory
factors NRF-1 and NRF-2, which are known to be important
for mitochondrial biogenesis [60], while Arany et al. suggest
that PGC-1α impacts mitochondrial biogenesis through its
co-activator oestrogen related receptor α (ERR-α) [62]. Kallio
et al. suggests a switch in fuel consumption to fatty acids
with the expression of PGC-1α [109]. In addition, PGC-1α
impacts the fiber types and oxidative capacity of muscle
fibers. The study by Lin et al. shows a 10% conversion of
type II fibers to type I fibers in PGC-1a transgenic mice [60].
VI. Notch signaling
Notch signaling is reported as a highly evolutionarily
conserved pathway that regulates many aspects of cellular
differentiation [110]. Pilar et al. suggests an inhibition of the
differentiation in myogenic cells under hypoxia, with the
stimulated expression of Notch downstream genes such as
Hes1 and Hey2 after 4 hours of hypoxia [110]. Deregulated
Notch signaling has been linked to tumor development,
though Notch can act either as an oncogene or as a
tumor-suppressor depending on the cell type [5]. Different
from Pilar’s results, Koning et al. reports an increase in
proliferation rate of cultured muscle stem cells (human
satellite cells) under hypoxia [111]. The gene expression of
transcription factors Pax7, Myf5 and Myod as well as gene
expression of structural proteins Myl1 and Myl3 in cultured
muscle stem cells are also up-regulated by hypoxia [111]. Our
transcriptomic study on hours of hypoxia in in vivo skeletal
muscles suggests Notch signaling as a pathway enriched with
gene changes, where Hes1 and Hey1 are significantly
down-regulated. This suggests the gene regulation in Notch
signaling pathway under hypoxic could be tissue specific.
The relationship between changes on gene expression and the
potential phenotype is not clear yet due to the complexity of
the translation of gene changes, especially for acute studies.
Summary
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Though skeletal muscles are relatively tolerant to hypoxia,
the current published data suggest that hypoxia induces a
number of responses in skeletal muscles including energy
rebalance, redox metabolism and others. These hypoxia
responses are dynamic. The hypoxia severity and duration
play a role on the kinetics of hypoxia responses. Previous
studies indicate that signaling pathways such as PI3K/Akt
signaling, AMPK/mTOR signaling, HIF signaling, PGC
signaling are widely involved in hypoxic responses in
skeletal muscles, accompanying with transcriptional changes.
The systemic relationship between transcriptional responses
and physiological responses is still unclear and could be a
challenging and interesting research direction.
Conflicting interests
The author has declared that no conflict of interests exists.
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8.
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Abbreviations
11. Lindholm ME, Rundqvist H. Skeletal muscle hypoxia-inducible
factor-1 and exercise. Experimental physiology 2015.
AKT: protein kinase B; AMPK: 5'-AMP-activated protein
kinase; AP-1: activator; protein 1; CAT: catalase; COPD:
chronic obstructive pulmonary disease; eNOS: endothelial
nitric oxide synthase; EPO: erythropoietin; ERK:
extracellular; signal-regulated kinase; ERR-α: oestrogen
related receptor α; GLUT: glucose transporter; HO-1: heme
oxygenase 1; HRE: hypoxia response element; JNK: c-jun
N-terminal kinase; MAPK: mitogen-activated protein kinase;
mTOR: mammalian target of rapamycin; NF-κb: nuclear
factor κb; NO: nitric oxide; NRF: nuclear respiratory factor;
PI3K:
phosphatidylinositol
3-kinase;
PGC:
peroxisome-proliferator-activated receptor-c coactivator;
ROS: reactive oxygen species; SOD: superoxide dismutase;
TFAM: mitochondrial transcription factor A; TFB1M:
mitochondrial
transcription
factor
B1;
TFB2M:
mitochondrial transcription factor B2; VEGF: vascular
endothelial growth factor.
12. Magalhaes J, Fraga M, Lumini-Oliveira J, Goncalves I, Costa M,
Ferreira R, et al. Eccentric exercise transiently affects mice
skeletal muscle mitochondrial function. Applied physiology,
nutrition, and metabolism = Physiologie appliquee, nutrition et
metabolisme 2013; 38:401-409.
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