Rev Bras Fisiol Exerc 2020;19(2):172-77
COMMENTED
ARTICLE
Comment
on: Bente Klarlund Peddersen, Physical activity and muscle-brain crosstalk
Leandro Paim da Cruz
Carvalho1, Jorge Luiz de Brito Gomes1
1Universidade Federal do Vale do São Francisco
(UNIVASF), Petrolina/PE, Brazil
Received
on: 2020, May 8; accepted 2020, May 9
Corresponding author: Leandro Paim da Cruz
Carvalho, UNIVASF, Colegiado de Educação Física, Av. José de Sá Maniçoba, S/N
Centro 56304-917 Petrolina PE Brazil
Leandro Paim da Cruz
Carvalho: leandroopaim@hotmail.com
Jorge Luiz de Brito Gomes: jorgelbritog@hotmail.com
In the recent article published in Nature Reviews Endocrinology – “Physical
activity and muscle-brain crosstalk” [1], the author - Bente
Klaurlund Peddersen, a
great reference in the study of skeletal muscle cell biology, contextualizes
the theme by citing great philosophers of the past and their perceptions about
the link between physical activity and the mind. Emphasizing the phrase of the
German philosopher Friedrich Nietzsche: “All great thoughts are conceived by
walking”.
Thus, since our ancestors, when starting to walk in a bipedal way, human
beings use a large amount of skeletal muscles as propelling agents for this action.
Muscles correspond to ~ 40% of the body mass of healthy adults, with percentage
changes throughout life. Muscles have functions beyond the mechanics of
movement, for example, endocrine. Thus, the stimulation of this tissue through
physical exercise (PE) promotes a great systemic impact [2,3].
Among these impacts, Peddersen BK [1]
highlights the growing volume of evidence converging that PE promotes brain
health benefits. In humans, PE increases blood flow to the hippocampus region
and even the size of the hippocampus [4]. The author points out that PE is also
essential to promote activation and increase of neural connections, in addition
to impacting the basic cognitive, motor and physiological functions involved in
mental health, such as appetite, sleep and mood [5-9].
For the effects of PE on the brain take place, two factors may be
involved: a) neurotrophins produced within the brain
and b) peripheral factors circulating in the bloodstream that may be due to
muscle-brain interaction [10]. One category of these circulating factors that
allow crosstalk between active muscles and brain function are the myokines.
Myokines are cytokines produced and secreted by the skeletal muscle, that may
act in an autocrine, endocrine or paracrine manner (they were baptized with
this name by Peddersen in 2003) [11].
Among the crosstalk pathways approached in the article, we have
separated three to detail in this article: 1) Cathepsin B – BDNF pathway, 2)
PGC1α - FNDC5 – BDNF pathway and 3) PGC1α – Kynurenine axis pathway.
I
- Cathepsin B – BDNF pathway
Cathepsin B is a myokine involved in improving the processes of
neurogenesis, cognition and memory mediated by PE in the hippocampus region.
The energy consumption promoted by the PE activates the AMP-activated protein
kinase (AMPK), which promotes the expression of the Ctsb
gene. The gene encodes cathepsin B, which is secreted into skeletal muscle and
released into the bloodstream [10].
Cathepsin B can cross the blood-brain barrier (BBB), where it stimulates
the expression of the messenger ribonucleic acid (mRNA) of the brain-derived
neurotrophic factor (BDNF). BDNF has a neuroprotective role against anxiety and
depression [10,12]. In addition, from exercise, concomitantly, there is also an
increase in doublecortin levels, which together with BDNF stimulate
neurogenesis [10,13].
The evidence mainly deals with aerobic exercise of moderate to high
intensity in animal models and in humans. In the article by Moon et al.
[10], cathepsin B levels increased significantly in humans who underwent
interval training on a treadmill at 70-90% of the maximum heart rate for 16
weeks.
On the other hand, when analyzing individuals who practice amateur rugby
in a chronic way (35 ± 15 years of practice), De la Rosa et al. [14]
found a lower serum concentration of cathepsin B in trained individuals,
compared to untrained ones, which may suggest chronic adaptation to PE and
greater efficiency of cathepsin signaling in trained individuals. In the same
study, BDNF was also measured, finding a similar response, lower serum
concentration in trained individuals than in untrained ones. In this case, the
authors consider that the lower concentration is due beyond better signaling,
to the fact that BDNF is also used for tissue repair, regulating satellite cell
differentiation and muscle regeneration [15].
Despite the robust evidence in the literature, about the ability of
resistance exercise to promote an increase in BNDF in humans [16,17], there is
no evidence in the about its efficiency in promoting neurogenesis in humans,
and in animal models, there are controversies [18,19]. Still, in our opinion,
this method of exercise should be encouraged to improve and maintain mental
health, as it promotes considerable cognitive gains in humans. For this, volume
seems to be an important variable, as evidenced in the study by Fortes et
al. [20], when investigating inhibitory control, a component of cognition,
in young individuals (18-31 years), demonstrated that greater volume (3 sets)
was better than lower volume (1 set) to stimulate adaptations in inhibitory
control.
II
- PGC1α – FNDC5 – BDNF pathway
Higher levels of Peroxisome proliferator-activated receptor gamma
coactivator-1 alpha (PGC1α) increase the expression of the membrane
protein Fibronectin type III domain containing 5 (FNDC5) in the muscle, also
present in highly oxidative tissues such as the heart and brain. During PE,
FNDC5 undergoes proteolytic cleavage by a protease not yet identified and is
secreted into the circulation in the form of the myokine irisin [17]. Irisin is
best known for its modulating effect on white adipose tissue, increasing
thermogenesis and energy expenditure, in addition to improving glucose
tolerance [22].
An interesting study has shown that cyclic aerobic exercise promotes
increased expression of the FNDC5 gene in the hippocampus of animal models
[23]. Another study demonstrated that the delivery of FNDC5 to the liver,
increased the concentration of circulating irisin and induced the expression of
the BNDF gene in the hippocampus [22]. This finding raised the hypothesis that
irisin can cross the BBB to stimulate the production of BDNF in the brain and
play a neurogenic, learning and reward-rewarding role.
The first question to ask is: After PE, would irisin released into the
bloodstream be, in fact, able to cross the BBB to stimulate the expression of
BDNF? The second, considering that FNDC5 is expressed not only in skeletal
muscle, but also in other oxidative tissues, if the first question is true:
Which tissue would contribute more to the expression of BDNF in the central
nervous system?
It is important to note that the discovery of the relationship between
exercise and FNDC5/irisin is recent [22], and there have even been questions
raised as to whether irisin was in fact an existing myokine in humans or a myth
derived from the low specificity of antibodies during analyzes by methods such
as western blot and ELISA [24]. The controversy was resolved after studies
demonstrated the detection of circulating irisin using mass spectrometry, a
robust method that does not depend on the quality of antibodies [25,26].
Two human studies found a correlation between serum irisin concentration
and cognition [21,26], however, a third study found no positive correlation
[27]. Although the author points out that the increase in irisin in the blood
is controversial, in our view, irisin seems to be a promising myokine due to
its diversified action. However, more research is needed analyzing irisin, PE
and its possible effects on the brain, especially in humans after cyclical
aerobic and resistance exercises, at different volumes and training
intensities.
III
- PGC1α – Kynurenine axis pathway
Tryptophan is an essential amino acid for protein synthesis, in addition
being the precursor of the neurotransmitter serotonin, fundamental for the
proper functioning of the brain and involved in the processes of regulating
mood, anxiety and cognition. Deficiency of serotonin is linked to development
of depression and, therefore, the prescription of physical exercise is
extremely important for people with mental health problems [28].
Most (~95%) of bioavailable tryptophan is metabolized to kynurenine, a
neurotoxic protein, which is commonly elevated in individuals with depression
[29]. This protein can cross the BBB, accumulating in the central nervous
system and may be related to neuronal death and neuroinflammation. An enzyme
called kynurenine aminotransferase converts kynurenine into kynurenic acid,
which in turn is not able to cross the BBB, thus exercising a neuroprotective
role [30].
PE promotes increased expression of PGC1α in skeletal muscle, this
protein mediates the metabolic effects of exercise on muscle and is also a
transcriptional co-activator of mitochondrial biogenesis and lipid metabolism
[31]. The increased expression of PGC1α stimulates the production of
kynurenine aminotransferase in skeletal muscle, increasing the conversion rate
of kynurenine to kynurenic acid, consequently reducing the levels of kynurenine
in the central nervous system, promoting a balance between neurotoxic and
neuroprotective substances, thus, presenting an antidepressant effect.
The literature points out that women produce more kynurenine than men,
this factor could help explain the two-fold rate of depression in women. In
addition, women who use oral contraceptives have a higher rate of depression
and a lower concentration of kynurenine acid than women who do not use it [32].
As with the first pathway presented, the evidence is concentrated on
cyclic aerobic exercise, requiring further studies analyzing the effect of
resistance exercise on this pathway, since resistance exercise activates PGC1α1,
while cyclic aerobic exercise activates another isoform, PGC1α4, and may,
thus present different results. Obese and type 2 diabetic individuals present
low levels of PGC1α expression [33]. The same takes place in elderly
individuals, therefore, studies evaluating the kynurenine/kynurenic acid
balance in these populations would be of great importance.
In the article, the author presents some important pathways of
interaction between skeletal muscle and the brain. Among which are the three
pathways highlighted in this article, which through myokines released by the
skeletal muscle from PE stimulus, are transported to the central nervous system
and can promote cognitive and memory improvements, in addition to stimulating
the process of neurogenesis and promote neuroprotective effect.
Research aiming to reveal the peripheral mechanisms of muscle-brain
crosstalk and the ability of exercise to modulate brain functioning, presents
great prospects for the future. The more in-depth knowledge of the molecular
processes of these and other pathways, can help direct the prescription of PE
in a more assertive way as prevention and treatment of diseases that affect the
central nervous system, as well as for other beneficial effects in different
populations.