ScientificWorldJournal. 2012; 2012: 584205.
Published online 2012 May 3. doi: 10.1100/2012/584205
PMCID: PMC3354688
Renewed Avenues through Exercise Muscle Contractility and Inflammatory Status
Abstract
Physical
inactivity leads to the accumulation of visceral fat and, consequently,
to the activation of a network of inflammatory pathways which may
promote development of insulin resistance, atherosclerosis,
neurodegeneration, and tumour growth. These conditions belong to the
“diseasome of physical inactivity”. In contrast, the protective effect
of regular exercise against diseases associated with chronic
inflammation may to some extent be ascribed to an anti-inflammatory
effect. The so called “acute exercise threshold”, the complex mixture of
several variables involved in exercise, such as type, volume,
frequency, and intensity range is capable of inducing positive
physiological adaptations and has been specifically addressed in the
recent literature. The major concern is related to the level of the
threshold: “exercise training shifts from a therapeutic adaptive
intervention to one with potential pathological consequences”.
Nonetheless, if the mechanical stimulus is too weak to disrupt cellular
homeostasis, training adaptations will not occur. Answering these
questions could present practical applications, especially during
inflammatory diseases associated with detrimental muscle effects and
could theoretically constitute a “new” therapeutic approach to
treat/improve an inflammatory state. This paper aims to describe
specific data from the literature regarding the effects of exercise on
inflammatory diseases in order to promote a more sophisticated
perspective on the anti-inflammatory effects of exercise.
1. Introduction
Daily
physical exercise offers protection against many corporal disorders,
which are responsible for numerous cases of mortality, including
cardiovascular, metabolic, and neural diseases. First of all, we know
that these disorders can coexist and share common mechanisms. In humans,
type 2 diabetes is associated with impaired cognitive function
(including learning, memory, and processing speed), accelerated
cognitive decline and high risk to dementia and Alzheimer's disease [1]. In a 3-year followup, van Elderen et al. [2]
observed that elderly patients with type 2 diabetes have accelerated
progression of brain atrophy with significant consequences in cognition
compared to subjects without type 2 diabetes, indicating that type 2
diabetes causes negative effects in neuronal integrity. Similarly,
hypertension has been linked to presence of white matter abnormalities
and Alzheimer's disease [3]. But in a study using an animal model of type 2 diabetes and hypertension, Yang et al. [3] showed that type 2 diabetes has a more pronounced effect on neurodegeneration than hypertension.
In addition, cancer patients with cachexia had higher mRNA expression of IL-6, TNF-R, and CRP levels [4],
the same alterations occurred in obese patients. Other diseases present
higher inflammatory markers. Duchene disease, is an example of a
genetic disorder and is associated with the elevated presence of
proinflammatory proteins [5].
In
summary, inflammation is related to the pathogenesis of all of these
diseases. Systemic low-grade inflammation is defined as two- to fourfold
elevations in circulating levels of proinflammatory and
anti-inflammatory cytokines, and chronic inflammation contributes to the
development of atherosclerosis, insulin resistance, tumor growth,
cancer, and neurodegeneration [6].
Many reports show the benefits of physical exercise improving type 2 diabetes [7], blood pressure [8], atherosclerosis and obesity [9], Alzheimer's disease and dementia [10], cognitive impairment [11], cancer [12], and other.
Even
though the positive effects of regular physical exercise in all these
disorders, some questions need to be clarified and have been discussed
in this paper, for example “what is the link of all these diseases?” and
“how can exercise influence these disorders?”. Thus, this paper focuses
on describing specific data from the literature regarding the effects
of exercise training on a wide range of inflammatory diseases to foster a
more sophisticated perspective on exercise and inflammation.
2. What Is the Relationship between Exercise and Inflammation?
Physical
inactivity leads to the accumulation of visceral fat and consequently
to the activation of a network of inflammatory pathways that promote the
development of insulin resistance, atherosclerosis, neurodegeneration,
tumour growth, and other diseases associated with physical inactivity.
According to Pedersen [13],
these diseases belong to the “diseasome of physical inactivity”, a
recent expression that describes the supra-cited effects of physical
inactivity on the onset of chronic inflammation. This network of
inflammatory pathways appears to be activated by environmental changes,
which began with the introduction of agriculture and the domestication
of animals about 10.000 years ago and occurred too recently to have
triggered adaptations in the human genome [14, 15].
Consequently, the occurrence of chronic diseases, which manifest
primarily in “modern civilizations,” is not due solely to genetic
factors but rather to hypokinesia associated with impaired nutritional
habits [16].
In
contrast, the protective effect of regular exercise against diseases
associated with chronic inflammation may to some extent be ascribed to a
small inflammatory effect, which reinforces anti-inflammatory response.
It was recently demonstrated by Pedersen's group that cytokines and
other peptides are expressed and released by contracting muscle fibers
and act to induce paracrine or endocrine effects [13].
Cytokines are a biologically active protein that holds several body
functions and are known products of the immune system and inflammation [17].
In line with the term “adipokines” which covers cytokines and peptides
produced and secreted by white adipose tissue (adipocytes), the term
“myokines” is created and is used to describe cytokines and other
peptides, which are produced and secreted by muscle fibers [13, 17].
For
many years, researchers are interested to find a link between muscle
fibers contraction and changes in several organs. The idea that
signalling pathways from contracting muscles to other organs that were
not only mediated by nervous system was supported by the findings from
electrical stimulation of paralyzed muscles in patients with spinal cord
injuries [18].
This research demonstrated the obvious: different compounds can be
secreted by muscle fibers (i.e., muscle-derived humoral factors) and
skeletal muscle should be classified as “endocrine organ” [13].
The
first identified and most studied is the gp130 receptor cytokine
interleukin-6 (IL-6). IL-6 is considered a myokine due to its increased
release (up to 100-fold) in plasma during physical exercise and is
dependent on exercise intensity, duration, the mass of muscle recruited,
and endurance capacity [13, 17, 19].
Since the discovery that mechanical stimuli of skeletal muscle is
capable of producing and secreting IL-6, this cytokine became well
studied in relation to exercise training [20].
In
summary, IL-6 mRNA is upregulated and its transcriptional rate is
enhanced in contracting skeletal muscle. In addition, protein content of
IL-6 and IL-6 released from skeletal muscle during exercise is
increased [17].
IL-6 acts locally in muscle fibers through activation of AMPK and when
released into the circulation, peripherally in several organs, mediates
its effects by biding to its receptor, gp130 [6].
Importantly,
IL-6 secreted during exercise exerts a strong inhibitory effect on the
expression of several proinflammatory cytokines, including an increased
anti-inflammatory interleukin-10 (IL-10) and decreased tumor necrosis
factor alpha (TNF-α) expressions, which may be strictly linked to insulin resistance [21]. Thus, regular exercise seems to be an interesting sine qua non condition
to avoid chronic diseases related to chronic inflammation in modern
societies and its protective effects may be ascribed to an
anti-inflammatory effect.
3. Exercise Threshold and Types
Chronic
aerobic exercise training or resistance training might presumably
induce the same degree of anti-inflammatory effects, whereby the degree
of effect appears to be related to exercise variables and the volume of
muscle mass involved in the mechanical stimuli [22].
Consequently, manipulations of exercise variables are vital to achieve
positive or negative effects. The so called “acute exercise threshold”
is defined as the complex mixture of several variables involved in
exercise, such as exercise type, volume, and intensity range, capable of
inducing positive physiological adaptations on remodelling. The major
concern related to the level of threshold is: “exercise training shifts
from a therapeutic adaptive intervention to one with potential
pathological consequences” [23].
Nonetheless, if the exercise stimulus is too weak to disrupt cellular
homeostasis (below this threshold), training adaptations may not occur.
This information is extremely relevant because different inflammatory
states might demand different types of exercise (i.e., resistance
exercise or endurance exercise) as well as quantity (volume of
training). This means that an inflammatory muscle state caused by
mutations in proteins inside the muscle (i.e., Duchenne muscular
distrophy) could demand distinct degree and type of exercise of an
inflammatory state provoked by excess of visceral fat and insulin
resistance. The differences in these responses may be explained by
tissue-specific responses (i.e., adaptation in skeletal muscle and
pathological and secondary in adipose tissue). For example, in Duchenne
dystrophy skeletal muscle structure is impaired because of the absence
of the protein dystrophin and an imbalanced mechanical stimuli may shift
from a “therapeutic adaptive intervention to one with potential
pathological consequences” [23].
In case of high adiposity, exercise will be intended to reduce visceral
fat, decreasing proinflammatory and increasing anti-inflammatory
proteins with more energy expenditure. Thus, the “acute exercise
threshold” should be extremely individualised in according to the type
of disease and exercise. However, in view of human genetic variability
and exercise training patterns, a practical standard consensus to the
mechanical stimuli to be applied in order to promote therapeutic effects
under inflammatory states is not available. However, providing a
bird's-eye view on what is known and unknown about the physiological and
biochemical mechanisms involved in exercise-induced anti-inflammatory
effects, the resulting map is surprisingly detailed in some areas such
as obesity and cancer, whereas other areas such as Duchenne distrophy
are still incompletely understood.
4. Would Exercise-Induced Chronic Effects Be Different than Acute?
According to Hawley et al. [24],
although the major perturbations to cellular homeostasis and muscle
substrate stores occur during exercise, the activation of several major
cellular responses for chronic training adaptations takes place during
the first few hours of recovery. These observations have contributed to
the establishment of a paradigm which states that many chronic training
adaptations are generated by the cumulative effects of the transient
events that occur during exercise and recovery from each (acute)
exercise bout [24].
In fact, the principles of exercise training assume that multiple
sessions of acute exercise, imposed within an appropriate frame time,
might stimulate and reinforce cellular and molecular processes that lead
to a compensatory response [25].
Although increased mechanical stimulation-induced tension associated
with resistance training has been shown to produce acute muscle damage
(increasing TNF-α concentrations in muscle tissue) [26],
repeated dynamic chronic resistance training may induce the known
“repeated bout effect” which abolishes the acute muscle damage [27].
Therefore, it is expected that acute exercise responses should be
completely different from those elicited by chronic exercise training [28].
For example, the attenuation of the acute phase inflammatory reaction
is a known effect mediated by multiple sets of acute exercise performed
on subsequent days [27],
which means that acute and chronic responses are tightly linked, but
the cellular responses generated after each occasion could be of a
completely different nature. Corroborating these evidences, it was
demonstrated that subjects submitted to 9 months of aerobic training
showed reduced plasma concentration of C-reactive protein [29].
Furthermore, although increased mechanical stimulation-induced tension
associated with resistance training has shown to produce acute muscle
damage and increased TNF-α levels in muscle tissue [26], regular resistance training has demonstrated significant anti-inflammatory effects (e.g., decreases in TNF-α expression) both in aerobic exercised rats [21], strength trained rats [30], and in humans [31].
5. Models of Resistance Training and Therapeutic Purposes in Healthy Conditions
5.1. Models of Resistance Training for Healthy Adults
The
importance of manipulating different resistance training variables
resides in the unevenness of the biological response on muscle and
nonmuscle cells that would be completely different depending on the
stimulus. From this perspective, it is also known that such challenges
to the exercised skeletal muscle increase several cellular adaptive
processes, including the secretion of mechano- and insulin-like growth
factors (MGF and IGF, resp.), which contribute to increased protein
synthesis through activation of mammalian target of rapamycin (mTOR)
pathway [32–34].
These factors also induce skeletal muscle damage and activate satellite
cells through the former process, when chemoattractant substances
(proinflammatory cytokines) are secreted by the muscle and inflammatory
cells in order to attenuate the damage process and potentiate
hypertrophy under physiologically healthy conditions [35, 36].
Thus, the discussion whether muscle damage is necessary to cause muscle
hypertrophy seems significant. In physiological conditions, it could be
a consequence of the choice of appropriate exercise variables ensuring
the gain (or loss) of muscle mass under specific mechanical stress
situations. However, if applied in other contexts (i.e., inflammatory
diseases), such choices could be even more delicate and elicit impaired
or increased responses in the signalling cascade involving skeletal
muscle hypertrophy and the presence or absence of increased
inflammation.
5.2. Specific Resistance Training: Therapeutic Purposes in Healthy Conditions
From
the above considerations, the relevant questions rise as the following
(1) Is there a necessity to cause muscle tissue damage under loading
conditions to produce muscle hypertrophy? (2) Would such muscle
hypertrophy in the absence of muscle damage be capable of inducing an
anti-inflammatory milieu in the muscle tissue? (3) What is the lowest
quantity of voluntary work capable to bring about such responses?
Answering these questions could present practical applications,
especially during inflammatory diseases associated with detrimental
muscle effects and could theoretically constitute a “new” therapeutic
approach to treated/improve this inflammatory state.
In
order to answer the first and third questions, there is some
speculation about the role of muscle damage in inducing hypertrophy.
Some studies have demonstrated that exercise-induced muscle damage may
not be a biological indicator of the hypertrophic response. Recently,
our group studied trained rats using a previously described resistance
training apparatus [37]
during 12 weeks, employing a “therapeutic” resistance training protocol
(i.e., resistance training protocol mainly composed of concentric
forces, low frequency/low volume of training, twice per week, 8
repetitions per day, twice per day). High loads determined by the
“volitional” percentage of maximum strength capacity (MVSC 80–95%) were
used to avoid muscle damage. Our results showed that plasma
phosphorylcreatine kinase was not modified after the 6th resistance
exercise session measured during several moments (preexercise and 15
minutes, 24 hours and 48 hours after the 6th resistance training
session). Moreover, at the end of the experiment (24 h after the last
resistance training session), muscle histology samples of both groups
(resistance-trained and control groups) were compared by eosin and
hematoxylin staining methods, and no signs of inflammatory cells or
muscle damage were visualised in either groups, nor were any centrally
localised nuclei present in the muscle fibers (an indicator of muscle
regeneration) [30].
In another study with the same model, muscle mass of resistance-trained
animals increased by ~13%, with a significant decrease in the gene
expression of atrogin-1 and MuRF-1 levels, the major muscle genes
involved in the activation of genetic programs leading to a decrease in
muscle mass through activation of the ubiquitin-proteasome system [38]. In contrast, a study by Flann et al. [39],
which aimed to test the hypothesis that the symptomatic muscle damage
is necessary to promote muscle remodeling in humans, demonstrated that
levels of creatine kinase (CK), self-reporting of initial perceived
soreness and exertion were significantly increased in the naive group
compared to pretrained. However, muscle size and strength gains did not
differ between groups and mean cross-sectional area and muscle strength
showed a similar increase in both groups. These results suggest that
remodeling and muscle hypertrophy can be initiated independently of any
discernible damage to the muscle.
Regarding
the second question, we studied rat muscles using the same resistance
training protocol, but focused on the pro- and anti-inflammatory milieu.
We did observe decreased protein expression of the proinflammatory
cytokine TNF-α and IL-10/TNF-α ratio [40], regarded as an important indicator of the inflammatory status and disease-associated morbidity [21, 41, 42].
Thus, our results are compatible with the view of the “therapeutic”
resistance exercise as a potential tool to promote anti-inflammatory
activity in the muscle. Additionally, gene expression of TLR4
signalling, which stimulates inflammatory cytokine production [43],
was also decreased by 60% in the plantaris muscle from trained rats, as
compared to control rats. Molecular chaperones, such as heat shock
protein 70 (Hsp70), have been found to increase under stressful
conditions [44] but they were not increased in our resistance-trained animals when compared with the sedentary ones. In humans, Ogawa et al. [45]
investigated the impact of 12 weeks of resistance exercise on
inflammation in the elderly and showed significantly reduced circulating
levels of C-reactive protein, Hsp70, and TNF-α. These proteins
were significantly associated with muscle thickness. In conclusion,
resistance training may assist in maintaining or improving muscle volume
and reducing low-grade inflammation. Together, although in animal
model, our results suggest the possibility of a “therapeutic” low
frequency, low volume and nonperiodised exercise schedule, predominantly
during a concentric resistance training protocol, as a way to achieve
muscle hypertrophy and to improve the anti-inflammatory milieu in the absence of indirect markers of muscle damage.
6. The Obesity-Cachexia Paradox: Role of Exercise Training
Both
cachexia and obesity may involve similar molecular defects since they
represent the two extremes of muscle loss. In this context, exercise
training seems to be a complementary therapeutic strategy which can
positively affect both obesity and cachexia conditions.
Several factors produced by the tumour and host tissues are suggested
to play a part in the mediation of muscle loss in cachexia. These
factors include proinflammatory cytokines such as TNF-α, IL-1β,
and IL-6 and factors produced by tumour cells, each of which can be
derived from the tumour itself and also from the host tissues [46].
Recently, several studies have characterised the relationship between
chronic inflammation and the increase in inflammation markers, notably
TNF-α, IL-1β, and IL-6, while transversal studies have
shown a positive correlation between physical inactivity and low-grade
systemic inflammation [13, 21, 47, 48], reinforcing the concept that a sedentary way of life is per se an inflammatory condition. A recent study by Sakurai et al. [49]
indicated that exercise training induces antioxidant effects on
visceral white adipose tissue (WAT) and that the levels of
inflammation-related adipokines, such as TNF-α and monocyte
chemotactic protein-1 (MCP-1) in WAT were lower in trained than in
sedentary rats. These effects were more pronounced in visceral than in
subcutaneous WAT.
Eventually,
frequent exercise training may abolish any kind of wasting in the
skeletal muscle, and there appears to occur a cross-talk among skeletal
muscles and adipose tissue such as occurances in cachexia induced by
cancer or obesity, preventing exacerbated secretion and release of
cytokines, mainly into adipose tissue. Recently, Zhou et al. [50]
demonstrated a direct connection between increased concentrations of
free fatty acids and increased rates of skeletal muscle proteolysis in C2C12
skeletal muscle cells. It is possible that this diminished
proinflammatory cytokine production in skeletal muscle and WAT plus
increased free fatty acids through exercise training could contribute to
the normalisation of skeletal muscle proteolysis in obese and cachectic
muscle. To reinforce such concept, sedentary rats presented increased
TNF-α in the WAT tissue (specifically in the mesenteric
tissue). In parallel, it was observed that IL-10 production almost is
doubled in trained rats, changing the IL-10/TNF-α ratio in favour of anti-inflammatory properties [21].
Taken together, these results indicate that exercise training seems to
be a comprehensive and low-cost alternative for the treatment of
obesity-/cachexia-related chronic inflammatory diseases.
7. Mutations Leading to Myopathy: Role of Exercise Intensity
In
Duchenne muscular dystrophy, mutations in the dystrophin gene lead to a
deficiency of this protein in muscle sarcolemma, a component of the
dystrophin-glycoprotein complex which forms an important link between
the cytoskeleton and the extracellular matrix in the muscle. When a
disruption of this link occurs due to a lack of dystrophin, a series of
complicated events follow each other, resulting in muscle degeneration,
significant weakness [51, 52],
repeated cycles of degeneration-regeneration, progressive inflammation,
and necrosis, with further destruction of the muscle fiber [53].
All of these observations have resulted in the suggestion that patients with Duchenne distrophy should not exercise [54, 55].
Moreover, intense exercise training seems to clearly induce muscle
damage in mdx mice, an animal model for Duchenne distrophy [55, 56].
However, it is unknown if mdx mice are physiologically capable to adapt
to exercise and what is the role of exercise intensity in these animals
with increased ROS production. To elucidate these questions, Kaczor et
al. [23]
examined the effect of low-intensity training on markers of oxidative
stress and observed that several markers of oxidative stress
(malondialdehyde and protein carbonyls) were decreased especially in the
fast-twitch muscles of mdx-trained mice when compared to the sedentary
group. On the other hand, low-intensity training did not induce positive
responses of the same oxidative stress markers in the wild-type
animals. A possible explanation for this observation is related to the
different exercise threshold presented by pathological versus
nonpathological mdx mice. Thus, changing exercise intensity, it was
decreased the oxidative stress markers in mdx mice challenging the
generally accepted view that exercise is deleterious to skeletal muscle
in the mdx model [23].
Nonetheless, it must be noted that the mdx mouse is a useful model to
study the molecular changes induced by the absence of dystrophin, but
clinical characteristics are manifested at a much lower intensity.
8. Conclusions and Perspectives
Exercise
training is certainly an important, low-cost and effective therapy to
treat several inflammatory diseases. However, most studies involving
exercise training therapy are short-term, transversal studies, that is,
the aforementioned results are of value but we do not know the impact of
such adaptations on the long term. Thus, it is possible that
appropriate adjustments to the training protocol may be an important
factor to consider in future human studies.
Regarding experimental research, a wide range of muscular and
nonmuscular diseases are related to inflammation, but in some cases
(Duchenne dystrophy for example), this relationship is a secondary
alteration related to a primary defect in muscle proteins. In this case,
should the effects of exercise efficacy be viewed in the same way as in
other inflammatory diseases? Finally, the endoplasmic reticulum of
secretory cells seems to be highly related with the induction of
inflammation in several diseases such as diabetes and other diseases
presenting a common denominator of chronic inflammation [57].
Thus, it is possible that the endoplasmic reticulum could be a next
target to be evaluated under exercise conditions. More studies,
especially those focused on protocol design and molecular responses,
will help to shed light on the mechanisms involved in such responses.
Acknowledgments
N.
E. Zanchi and H. Nicastro are supported by Fundação de Amparo à
Pesquisa do Estado de São Paulo, FAPESP (Grants number 08/51090-1 and
10/07062-3).
References
1. Allen
KV, Frier BM, Strachan MWJ. The relationship between type 2 diabetes
and cognitive dysfunction: longitudinal studies and their methodological
limitations. European Journal of Pharmacology. 2004;490(1–3):169–175. [PubMed]
2. van
Elderen SGC, de Roos A, de Craen AJM, et al. Progression of brain
atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. Neurology. 2010;75(11):997–1002. [PubMed]
3. Yang
C, DeVisser A, Martinez JA, et al. Differential impact of diabetes and
hypertension in the brain: adverse effects in white matter. Neurobiology of Disease. 2011;42(3):446–458. [PubMed]
4. DeJong
CH, Busquets S, Moses AG, et al. Systemic inflammation correlates with
increased expression of skeletal muscle ubiquitin but not uncoupling
proteins in cancer cachexia. Oncology Reports. 2005;14(1):257–263. [PubMed]
5. Piers
AT, Lavin T, Radley-Crabb HG, Bakker AJ, Grounds MD, Pinniger GJ.
Blockade of TNF in vivo using cV1q antibody reduces contractile
dysfunction of skeletal muscle in response to eccentric exercise in
dystrophic mdx and normal mice. Neuromuscular Disorders. 2011;21(2):132–141. [PubMed]
6. Brandt C, Pedersen BK. The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases. Journal of Biomedicine and Biotechnology. 2010;2010:6 pages. Article ID 520258. [PMC free article] [PubMed]
7. Zanuso
S, Jimenez A, Pugliese G, Corigliano G, Balducci S. Exercise for the
management of type 2 diabetes: a review of the evidence. Acta Diabetologica. 2010;47(1):15–22. [PubMed]
8. Totsikas
C, Röhm J, Kantartzis K, et al. Cardiorespiratory fitness determines
the reduction in blood pressure and insulin resistance during lifestyle
intervention. Journal of Hypertension. 2011;29(6):1220–1227. [PubMed]
9. Lim S, Despres JP, Koh KK. Prevention of atherosclerosis in overweigh/obese patients. Circulation Journal. 2011;75:1019–1027. [PubMed]
10. Vidoni ED, Townley RA, Honea RA, Burns JM. Alzheimer disease biomarkers are associated with body mass index. Neurology. 2011;77(21):1913–1920. [PMC free article] [PubMed]
11. Feil
DG, Zhu CW, Sultzer DL. The relationship between cognitive impairment
and diabetes self-management in a population-based community sample of
older adults with Type 2 diabetes. Journal of Behavioral Medicine. In press. [PubMed]
12. Lynch
BM, Friedenreich CM, Winkler EAH, et al. Associations of objectively
assessed Physical activity and sedentary time with biomarkers of breast
cancer risk in postmenopausal women: findings from NHANES (2003–2006) Breast Cancer Research and Treatment. 2011;130(1):183–194. [PubMed]
13. Pedersen BK. The diseasome of physical inactivity—and the role of myokines in muscle—fat cross talk. The Journal of Physiology. 2009;587(23):5559–5568. [PMC free article] [PubMed]
14. Cordain L, Eaton SB, Sebastian A, et al. Origins and evolution of the Western diet: health implications for the 21st century. The American Journal of Clinical Nutrition. 2005;81(2):341–354. [PubMed]
15. Frassetto
L, Morris RC, Jr., Sellmeyer DE, Todd K, Sebastian A. Diet, evolution
and aging—the pathophysiologic effects of the post-agricultural
inversion of the potassium-to-sodium and base-to-chloride ratios in the
human diet. European Journal of Nutrition. 2001;40(5):200–213. [PubMed]
16. Chakravarthy
MV, Booth FW. Eating, exercise, and “thrifty” genotypes: connecting the
dots toward an evolutionary understanding of modern chronic diseases. Journal of Applied Physiology. 2004;96(1):3–10. [PubMed]
17. Pedersen
BK, Febbraio M. Muscle-derived interleukin-6—a possible link between
skeletal muscle, adipose tissue, liver, and brain. Brain, Behavior, and Immunity. 2005;19(5):371–376. [PubMed]
18. Kjr
M, Pollack SF, Mohr T, et al. Regulation of glucose turnover and
hormonal responses during electrical cycling in tetraplegic humans. American Journal of Physiology. 1996;271(1):R191–R199. [PubMed]
19. Castell
LM, Poortmans JR, Leclercq R, Brasseur M, Duchateau J, Newsholme EA.
Some aspects of the acute phase response after a marathon race, and the
effects of glutamine supplementation. European Journal of Applied Physiology and Occupational Physiology. 1997;75(1):47–53. [PubMed]
20. Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. American Journal of Physiology. 2003;285(2):E433–E437. [PubMed]
21. Lira
FS, Rosa JC, Yamashita AS, Koyama CH, Batista ML, Jr., Seelaender M.
Endurance training induces depot-specific changes in IL-10/TNF-α ratio in rat adipose tissue. Cytokine. 2009;45(2):80–85. [PubMed]
22. Mathur N, Pedersen BK. Exercise as a mean to control low-grade systemic inflammation. Mediators of Inflammation. 2008;2008:6 pages. Article ID 109502. [PMC free article] [PubMed]
23. Kaczor
JJ, Hall JE, Payne E, Tarnopolsky MA. Low intensity training decreases
markers of oxidative stress in skeletal muscle of mdx mice. Free Radical Biology and Medicine. 2007;43(1):145–154. [PubMed]
24. Hawley
JA, Hargreaves M, Zierath JR. Signalling mechanisms in skeletal muscle:
role in substrate selection and muscle adaptation. Essays in Biochemistry. 2006;42:1–12. [PubMed]
25. Haddad F, Adams GR. Selected contribution: acute cellular and molecular responses to resistance exercise. Journal of Applied Physiology. 2002;93(1):394–403. [PubMed]
26. Del
Aguila LF, Krishnan RK, Ulbrecht JS, et al. Muscle damage impairs
insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase in human
skeletal muscle. American Journal of Physiology. 2000;279(1 42-1):E206–E212. [PubMed]
27. Chen TC, Hsieh SS. Effects of a 7-day eccentric training period on muscle damage and inflammation. Medicine and Science in Sports and Exercise. 2001;33(10):1732–1738. [PubMed]
28. Rosa
Neto JC, Lira FS, Oyama LM, et al. Exhaustive exercise causes an
anti-inflammatory effect in skeletal muscle and a pro-inflammatory
effect in adipose tissue in rats. European Journal of Applied Physiology. 2009;106(5):697–704. [PubMed]
29. Mattusch
F, Dufaux B, Heine O, Mertens I, Rost R. Reduction of the plasma
concentration of C-reactive protein following nine months of endurance
training. International Journal of Sports Medicine. 2000;21(1):21–24. [PubMed]
30. Zanchi
NE, Lira FS, Seelaender M, Lancha-Jr AH. Experimental chronic
low-frequency resistance training produces skeletal muscle hypertrophy
in the absence of muscle damage and metabolic stress markers. Cell Biochemistry and Function. 2010;28(3):232–238. [PubMed]
31. Pedersen BK, Saltin B. Evidence for prescribing exercise as therapy in chronic disease. Scandinavian Journal of Medicine and Science in Sports. 2006;16(supplement 1):3–63. [PubMed]
32. Esser K. Regulation of skeletal muscle size, regeneration and repair. Journal of Musculoskeletal Neuronal Interactions. 2008;8(4):335–336. [PubMed]
33. Miyazaki M, Esser KA. Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals. Journal of Applied Physiology. 2009;106(4):1367–1373. [PMC free article] [PubMed]
34. Zanchi NE, Lancha AH., Jr. Mechanical stimuli of skeletal muscle: implications on mTOR/p70s6k and protein synthesis. European Journal of Applied Physiology. 2008;102(3):253–263. [PubMed]
35. Koh TJ, Pizza FX. Do inflammatory cells influence skeletal muscle hypertrophy? Frontiers in Bioscience. 2009;1:60–71. [PubMed]
36. Serrano
AL, Baeza-Raja B, Perdiguero E, Jardí M, Muñoz-Cánoves P. Interleukin-6
is an essential regulator of satellite cell-mediated skeletal muscle
hypertrophy. Cell Metabolism. 2008;7(1):33–44. [PubMed]
37. Klitgaard H. A model for quantitative strength training of hindlimb muscles of the rat. Journal of Applied Physiology. 1988;64(4):1740–1745. [PubMed]
38. Zanchi
NE, de Siqueira Filho MA, Lira FS, et al. Chronic resistance training
decreases MuRF-1 and Atrogin-1 gene expression but does not modify Akt,
GSK-3β and p70S6K levels in rats. European Journal of Applied Physiology. 2009;106(3):415–423. [PubMed]
39. Flann KL, Lastayo PC, McClain DA, Hazel M, Lindstedt SL. Muscle damage and muscle remodeling: no pain, no gain? Journal of Experimental Biology. 2011;214(4):674–679. [PubMed]
40. Zanchi
NE, Lira FS, de Siqueira Filho MA, et al. Chronic low frequency/low
volume resistance training reduces pro-inflammatory cytokine protein
levels and TLR4 mRNA in rat skeletal muscle. European Journal of Applied Physiology. 2010;109(6):1095–1102. [PubMed]
41. Jung
SH, Park HS, Kim KS, et al. Effect of weight loss on some serum
cytokines in human obesity: increase in IL-10 after weight loss. Journal of Nutritional Biochemistry. 2008;19(6):371–375. [PubMed]
42. Petersen AMW, Pedersen BK. The anti-inflammatory effect of exercise. Journal of Applied Physiology. 2005;98(4):1154–1162. [PubMed]
43. McFarlin
BK, Flynn MG, Campbell WW, Stewart LK, Timmerman KL. TLR4 is lower in
resistance-trained older women and related to inflammatory cytokines. Medicine and Science in Sports and Exercise. 2004;36(11):1876–1883. [PubMed]
44. Benjamin IJ, McMillan DR. Stress (heat shock) proteins molecular chaperones in cardiovascular biology and disease. Circulation Research. 1998;83(2):117–132. [PubMed]
45. Ogawa
K, Sanada K, MacHida S, Okutsu M, Suzuki K. Resistance exercise
training-induced muscle hypertrophy was associated with reduction of
inflammatory markers in elderly women. Mediators of Inflammation. 2010;2010:7 pages. Article ID 171023. [PMC free article] [PubMed]
46. Bing C, Trayhurn P. New insights into adipose tissue atrophy in cancer cachexia. Proceedings of the Nutrition Society. 2009;68(4):385–392. [PubMed]
47. Lira FS, Rosa JC, Zanchi NE, et al. Regulation of inflammation in the adipose tissue in cancer cachexia: effect of exercise. Cell Biochemistry and Function. 2009;27(2):71–75. [PubMed]
48. Lira
FS, Rosa JC, Dos Santos RV, et al. Visceral fat decreased by long-term
interdisciplinary lifestyle therapy correlated positively with
interleukin-6 and tumor necrosis factor-α and negatively with adiponectin levels in obese adolescents. Metabolism. 2011;60(3):359–365. [PubMed]
49. Sakurai
T, Izawa T, Kizaki T, et al. Exercise training decreases expression of
inflammation-related adipokines through reduction of oxidative stress
in rat white adipose tissue. Biochemical and Biophysical Research Communications. 2009;379(2):605–609. [PubMed]
50. Zhou
H, Liu X, Liu L, et al. Oxidative stress and apoptosis of human brain
microvascular endothelial cells induced by free fatty acids. Journal of International Medical Research. 2009;37(6):1897–1903. [PubMed]
51. Wallace GQ, McNally EM. Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies. Annual Review of Physiology. 2009;71:37–57. [PubMed]
52. Vainzof M, Ayub-Guerrieri D, Onofre PCG, et al. Animal models for genetic neuromuscular diseases. Journal of Molecular Neuroscience. 2008;34(3):241–248. [PubMed]
53. Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447(7140):87–91. [PubMed]
54. Eagle M. Report on the muscular dystrophy campaign workshop: exercise in neuromuscular diseases Newcastle, January 2002. Neuromuscular Disorders. 2002;12(10):975–983. [PubMed]
55. Carter
GT, Abresch RT, Fowler WM., Jr. Adaptations to exercise training and
contraction-induced muscle injury in animal models of muscular
dystrophy. American Journal of Physical Medicine and Rehabilitation. 2002;81(11, supplement):S151–S161. [PubMed]
56. Granchelli JA, Pollina C, Hudecki MS. Pre-clinical screening of drugs using the mdx mouse. Neuromuscular Disorders. 2000;10(4-5):235–239. [PubMed]
57. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. Journal of Clinical Investigation. 2006;116, article 2308 [PMC free article] [PubMed]
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