Nitric Oxide 26 (2012) 89–94
Contents lists available at SciVerse ScienceDirect
Nitric Oxide
journal homepage: www.elsevier.com/locate/yniox
Review
Nitric oxide: Is it the cause of muscle soreness?
Zsolt Radak a,b,⇑, Hisashi Naito b, Albert W. Taylor a,c, Sataro Goto b
a
Semmelweis University, Research Institute of Sport Science, Budapest, Hungary
Department of Exercise Physiology, School of Health and Sport Science, Juntendo University, Chiba, Japan
c
Faculty of Health Sciences, The University of Western Ontario, London, Canada
b
a r t i c l e
i n f o
Article history:
Received 17 November 2011
Revised 14 December 2011
Available online 28 December 2011
Keywords:
Exercise
Skeletal muscle
Muscle damage
Pain
Hormesis
a b s t r a c t
Skeletal muscle hosts all of the isoforms of nitric oxide synthase (NOS). It is well documented that nitric
oxide (NO) regulates force generation and satellite cell activation, and therefore, damage repair of skeletal
muscle. NO can also activate nociceptors of C-fibers, thereby causing the sensation of pain. Although
delayed-onset of muscle soreness (DOMS) is associated with decreased maximal force generation, pain
sensation and sarcomere damage, there is a paucity of research linking NO and DOMS. The present
mini-review attempts to elucidate the possible relationship between NO and DOMS, based upon current
literature.
Ó 2011 Published by Elsevier Inc.
Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Muscle soreness-induced suppression of maximal force generation and the potential
Is nitric oxide involved in muscle soreness? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Muscle damage and repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Although, delayed-onset of muscle soreness (DOMS) has been
extensively studied, the phenomenon is still not completely understood. DOMS peaks about 1–3 days after unaccustomed exercise
bouts, the result of lengthening contractions [1,2]. The etiology of
DOMS is still vague [3], even after a number of different hypotheses have described the most important symptoms, which are, pain,
decreased maximal force generation, and altered permeability of
sarcolemma. It was suggested long ago, that DOMS is associated
with mechanical damage. In 1977 Abraham [4] measured the ratio
of hydroxyproline/creatinine in the urine samples of subjects with
⇑ Corresponding author at: Institute of Sport Science, Faculty of Physical
Education and Sport Science, Semmelweis University, Alkotas u. 44, TF, Budapest,
Hungary. Fax: +36 1 356 6337.
E-mail addresses: [email protected], [email protected] (Z. Radak).
1089-8603/$ - see front matter Ó 2011 Published by Elsevier Inc.
doi:10.1016/j.niox.2011.12.005
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and without muscle soreness, and the increased ratio indicated significant damage to connective tissue. From biopsy samples, Friden
and co-workers [5,6] reported that DOMS-associated muscle damage included intermyofibrillar sarcoma disturbances, and Z-band
streaming, especially in Type 2 fibers [7–10]. This observation
was confirmed later using magnetic resonance techniques
[10,11]. Edema formation has also been observed in subjects suffering from DOMS [12]. A large increase in creatine kinase (CK)
and myoglobin concentrations in the circulation are two of the
most often used associated markers of DOMS and indicate
increased permeability of the sarcolemma [13–18]. However, it
has been reported that the magnitude of DOMS is not always associated with the magnitude of other markers of muscle damage
[19].
In normal conditions, tissue damage is associated with inflammation, which, besides the well known beneficial effects, could
also result in some of the discomforts of DOMS [20]. Based upon
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Z. Radak et al. / Nitric Oxide 26 (2012) 89–94
this hypothesis, naproxen sodium, which is a potent anti-inflammatory drug, has been used to attenuate the consequences of
DOMS. However, significant effects have not been observed on
the extent of pain, CK release, or force generation [21]. Among
the indirect markers of DOMS, the altered ratio of oxidized to reduced glutathione indicates that, as a result of inflammation or calcium efflux, reactive oxygen species (ROS) are generated [3,22].
The generation of ROS is often observed during aerobic exercise,
in which the mitochondrial electron transport chain is one of the
main source of ROS [23–25]. However, the fact that eccentric muscle action with high tension and relatively low oxygen demand,
such as downhill running, more readily causes DOMS than running
with the same intensity on a flat surface [22], suggests that the
main source of the generated free radicals is not the mitochondrial
electron transport chain, but rather is due to secondary sources
such as inflammatory agents [26].
The possible involvement of NO in DOMS was originally suggested by Radak et al. [27]. In that study the subjects developed
DOMS after eccentric exercise. NO was measured from skeletal
muscle biopsy samples of control subjects and subjects suffering
from DOMS. The NO content was evaluated using electron spin resonance methodology, and an approximate 30% increase in NO levels was detected in skeletal muscle of subjects suffering from
DOMS. This finding was associated with a significant decrease in
maximal force generation. Since that time a number of important
studies have been published on the role of NO in skeletal muscle
function [28,29], and the findings include down regulation of force
production [30,31], sensation of pain, and/or damage repair [32–
36]. Although these studies were not always conducted during
DOMS, the findings could be readily applicable to DOMS. Therefore,
the present review attempts to highlight the role of NO in DOMS,
especially in conditions that are associated with factors of DOMS,
such as decreased maximal force generation, sensation of pain,
and damage repair.
Muscle soreness-induced suppression of maximal force
generation and the potential role of nitric oxide
Tiidus and Ianuzzo [37] reported that, in subjects with a high
degree of muscle soreness, individuals were unable to lift weights
corresponding to 90% max, for even one repetition, 48 h post-exercise. There is general agreement that DOMS results in decreased
force generation 1–4 days after DOMS-induced exercise bouts
[38,39], although Nosaka et al. [19] reported dissociation between
the magnitude of DOMS and loss of muscle strength.
Our group was the first to describe a possible relationship between a DOMS-associated decrease in maximal force generation
and NO concentration [27]. We have suggested that the DOMSinduced increase in NO formation that could suppress force generation was, at least in some part, a protective mechanism to prevent
further damage induced by maximal contraction. However, at that
time it was unclear whether NO was capable of down-regulating
skeletal muscle contraction.
NO is produced by nitric oxide synthase (NOS) from L-arginine
following an oxygen dependent process. Skeletal muscle hosts
the three types of NO isoforms: inducible NO (iNO), endothelial
NO (eNO), and neuronal NOS (nNO) [40]. The main NO generating
enzyme in skeletal muscle is nNO, which is encoded to dystrophin
[29,41]. It is quite clear that NO can regulate muscular function,
force generation, and even affect the structure of skeletal muscle
[42,43]. This regulatory process includes the NO mediated reversible inhibition of cytochrome oxidase, which affects oxygen uptake
[44]. NO can control the IGF-I/p70 S6 kinase signaling pathway
during muscle growth [45]. NO has also been implicated in protein
S-nitrosylation of skeletal muscle and therefore, could modulate
ATP-ase activity [46], as well as an exaggerated exercise-induced
fatigue response [47]. It is clear that sarcolemmal nNO is an important regulator of blood flow to active skeletal muscle [29]. It
appears that during eccentric exercise the induction of nuclear factor kappa-B, which is one of the main mediators of the inflammatory process [48], modulates the transcription of all of the isoforms
of NO [49]. This observation could illustrate an important link
between DMOS-inflammation and NO induction. In addition, the
exercise induced NO generation appears to be important for the
induction of interleukin-6, interleukin-8, hem oxigenase and
HSP78 [50]. Indeed, NO, with a relatively long half-life, is an important signaling molecule [44,51,52]. However, because of the gaseous nature of NO, a transmitter would be advantageous to work
specifically on targeted sites. Indeed, cyclic guanosine monophosphate (cGMP) is generated by NO, transmits the signal, and readily
turns on downstream targets [53].
It is known that both inhibitors and donors of NO can result in
decreased force generation [54], which demonstrates that the dose
response of NO follows a bell-shaped hormetic curve [55–57]. The
hormesis curve is a dose–response phenomenon [58,59] which can
be described by low dose caused activation and high dose caused
inhibition, a phenomenon which is generally true for other free
radicals [58,60,61]. Although, nNO are readily up-regulated by
exercise training [53] an increased level of NO or cGMP, can interact via a variety of pathways, to down regulate force production.
One of the first studies to report a causative link between NO generation and decreased force generation showed that iNO inhibitions maintained force levels in the diaphragm [62]. Andrade and
co-workers [63] have studied the effects of NO donors and cGMP
inhibitors on Ca++ sensitivity and force generation of single fibers,
and concluded that NO can impair Ca++ sensitivity, especially on
actin filaments. Similarly to these earlier findings, Galler et al.
[64] reported that, in skinned fibers, increased levels of NO
resulted in decreased force generation through direct interaction
of NO with force-generating fibers. It was also revealed that NO,
through oxidizing contractile thiol proteins and by the depression
of actomyosin ATP-ase, could mediate force development [64].
Moreover, increased levels of NO have been shown, in rabbit skeletal muscle, to result in a decreased number of cross-bridges and
hence decreased force generation [65]. NO levels also negatively
affect the force generation of cardiomyocytes [66], suggesting that
NO and cGMP could have similar affects on contractile function in
myocardium as in skeletal muscle. However, there are few studies
which report on the effects of NO mediated changes after eccentric
exercise and only one in which the investigators studied the possible link between NO and force generation [27]. In another study, in
which the effects of eccentric exercise were studied on NO content,
it has been shown that eccentric exercise increases nitrate concentration [67], and iNO activity [68–70] but the link between eccentric exercise induced NO and force production requires further
study. Nonetheless, DOMS can be induced by eccentric exercise
or by an unaccustomed exercise load [21,71,72]. The results of
these studies would seem to suggest that enhanced NO production
could impair force production in skeletal muscle [57] and the muscle soreness-associated increase could be a protective mechanism
for skeletal muscle to prevent the possibility of maximal force generation and extensive damage [27].
Is nitric oxide involved in muscle soreness?
In a critical review, Amstrong [1] suggested that the pain, during DOMS, is due to the activity of macrophages and possibly the
by-products of damage-induced exercise that accumulate in the
interstitium, activating the endings of group-IV sensory neurons.
The activation of macrophages could be a result of inflammation,
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Z. Radak et al. / Nitric Oxide 26 (2012) 89–94
which would lead to the involvement of prostaglandins and the related pain. However, the supplementation of prostaglandin suppressing agent flurbiprofen did not significantly affect the
sensation of pain, which suggests the existence of other factors
[15]. Intramuscular fluid pressure, measured after concentric and
eccentric bouts of muscle contraction, and two days after the exercise, increased with eccentric contraction, and was associated with
the resultant pain [5]. Thus, the investigators suggested that eccentric exercise-induced intramuscular fluid mediated pressure is a
causative factor of pain sensation. In 1994 Miles and Clarkson
[73] stated that the exact cause of DOMS-related pain remained
a mystery. The theory of prostaglandin mediated pain gained support later on, when it was shown that indomethacin treatment decreased this eccentric exercise mediated pain. The pain was
probably sensed by polymodal-type nociceptors [74]. However, it
must be noted that aspirin supplementation, (a potent inhibitor
of prostaglandin synthesis) has been tested a number of times
and found not to be effective to attenuate DOMS [75]. Glutamate
could be one mediator of DOMS-associated pain, since DOMS increases glutamate concentration significantly in skeletal muscle
(when measured by microdialysis), and supplementation of hypertonic saline causes a significant increase in dialysate glutamate
concentration and decreased pain [76]. The presence of glutamate
at the site of inflammation in the skeletal muscle is not surprising,
since it is an important fuel for inflammatory cells [77].
Besides nociceptors, opioid receptors could also be activated,
since the administration of morphine-6-glucuronide has been
shown to decrease DOMS-associated pain [78]. Both nociceptors
and most of the opioid receptors are sensitive to NO. A recent study
reports that DOMS-associated pain is due to the mechanical stress
related activation of nociceptors by bradykinin (which can produce
NO) and neuro growth factor prolongs this pain [79].
The available information suggests that DOMS-associated pain,
sensed by opioid receptors, mechano and nociceptors, can be activated by increased fluid pressure, prostaglandin, bradykinin, glutamate, ATP, or NO, and the pain is sustained by neuro growth factor
(Fig. 1). However, it is not clear whether the joint activation of opioid, mechano and nociceptors are obligatory to DOMS. The unaccustomed exercise associated sensation of pain appears to be
Muscle damage
very complex and, despite significant findings on the nature of substrates that are able to cause pain, it remains unknown when and
how the receptors are activated and the possibility of cross-talking
between substances is still a mystery.
Muscle damage and repair
As mentioned above, unaccustomed exercise-induced muscle
damage was observed decades ago, but, interestingly, mechanical
studies on the repair process are lacking. Many observations have
been made about the level of fitness, stretching, or physiotherapeutic treatments which can decrease DOMS and facilitate repair
(please see the reviews [80–85]).
We hypothesize that NO, which can mediate decreased force
production and elevate pain sensation during DOMS, plays a very
important role in the repair of muscle damage. One of the first
investigations on the role of NO in skeletal muscle damage was reported by Anderson [35] who mechanically crushed muscle of
wild, NO knock-out or NO inhibited mice and observed very different repair processes to reveal the importance of NO in damage repair. It followed that NO facilitates the activation of satellite cells,
which are located in the basal lamina of skeletal muscle, and this is
one of the first steps in the repair process. Moreover, it appears
that the beneficial function of NO in damage repair is not just restricted to satellite cell proliferation and differentiation but also
to fusion. Hence, NO and the signaling agent of NO, cGMP, the
antagonist of myostatin, activate follistatin [86], which is a negative regulator of myogenesis. Despite the well described role of
NO in the repair of muscle injury, it is possible that the mechanism
controlling repair after unaccustomed exercise-induced damage
might be different from those after crush injury. Interestingly,
treadmill running related overuse of tendons results in increased
NO production, which suggests a role in the repair process [87].
The induction of mechanical damage to gastrocnemius muscle
has been shown to result in increased NO formation, which is believed to initiate a signaling process for damage repair [88]. In
addition, the importance of NO to muscle function, has been demonstrated as NO inhibition resulted in severe reduction in walking
speed of rats [89].
Therefore, one can suggest that NO, which is generated during
muscle contraction as a result of nNO [29], eNO [90–92] and iNO
[93,94] activation, could cause decreased force generation, pain
as a protective mechanism but also obligatory to the repair process
PAIN
Macrophages
Muscle soreness
iNOS
Circulation eNOS
Brain
Dorsal root ganglion
NO
Bradykinin
Afferent neuron
Fluid
Pressure
NGF
Spinal cord
NO
NO generation
Glutamate
Opioid receptor
nNOS
?
nociceptors
Skeletal Muscle
Fig. 1. The theoretical mechanism of muscle soreness-induced pain sensation.
Nociceptor sensed activation can result IN pain via C-type afferent fibers, while the
opioid receptor induced pain is mediated by primary neurons. Nociceptors can be
activated by a number of agents including bradykinin, ATP, glutamate and NO. NGF
has been suggested to be involved in the prolongation of pain. NO can be produced
by iNO (macrophages), by eNO as a result of blood flow mediated regulation, and by
nNO located in dystrophin and the Golgi system. Intramuscular fluid pressure might
also cause pain, adding to the complex mechanism of pain sensation.
Pain
?
Regeneration via
Satellite cell and
Follistatin
activation
Decreased forced generation
Fig. 2. The hypothetical model shows that the muscle soreness induced decreases
in force generation, pain and regeneration could be due to nitric oxide. Most
probably the DOMS-associated discomfort is a complex multifactoral mechanism,
but nitric oxide is one important, so far neglected molecule, that plays an important
role in DOMS. Question marks indicate other mechanisms (other than NO) which
could also be implicated in pain, and decreased force generation.
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Z. Radak et al. / Nitric Oxide 26 (2012) 89–94
by satellite cell activation, proliferation, and fusion by the activating follistatin (Fig. 2). This suggestion is in accordance with the
observation that mdx mice (lack of dystrophin ancored nNO, thus
genetically mimicing Duchenne muscular dystrophy), suffer from
impaired skeletal muscle repair [95]. The fact that nNO splice variants such as nNOl and nNOb (located in the golgi system) deficient
mice are extremely myopathic [29], further supports the role of NO
in muscle damage repair and muscle physiology. Moreover, nNO is
involved in eccentric exercise and caused damage because it has
been observed that nNO blocker supplementation increases the
eccentric exercise induced damage of desmin and dystrophin [96].
Conclusion
DOMS is a very complex mechanism, with well characterized
symptoms, including decreased maximal force generation
1–3 days post-exercise, pain sensation and mechanical damage to
skeletal muscle and connective tissue. Although, the etiology of
DOMS cannot be described by a single agent, the present review
emphasizes the possible role of NO in DOMS, which indeed could
be important in decreased maximal force generation, pain, and
damage repair. Despite the well established role of NO in muscle
physiology, more research is necessary to further clarify its effects
in DOMS.
Perspectives
It is well established that unaccustomed exercise induces muscle damage and pain. NO could be one of the causes of pain sensation, hence NO-blockers or NO binding agents could have the
potential to attenuate pain. However, it must be mentioned that
pre-treatment with NO inhibitors may result in reduced blood flow
in skeletal muscle, resulting in reduced performance. Therefore, in
order to increase endurance capacity one may have to pay the price
of a little pain.
On the other hand, NO appears to be important for the activation of satellite cells that are required for damage repair. Hence,
NO donors could promote damage repair. Therefore, it can be
hypothesized that pre-treatment of NO inhibitor and post-treatment of NO activator could have beneficial effects on DOMS. There
is a wide array of commercially available products that aim to increase blood flow by activating NO production in skeletal muscle,
but one has to note that these products can cause hypotension
and/or redistribution of blood away from the skeletal muscle.
Therefore, the manipulation of NO production in skeletal muscle
is not without risk, and muscle specific NO stimulators could have
the potential to increase blood flow during exercise and by the
activation of satellite cells and follistatin stimulate damage repair
and even muscle hypertrophy.
Acknowledgment
The present work was supported by Hungarian grants by ETT
38388, OTKA (K75702), TéT JAP13/02, JSPS (L-10566) awarded to
Z. Radák.
References
[1] R.B. Armstrong, Mechanisms of exercise-induced delayed onset muscular
soreness: a brief review, Med Sci Sports Exerc 16 (1984) 529–538.
[2] K.K. McCully, Exercise-induced injury to skeletal muscle, Fed Proc 45 (1986)
2933–2936.
[3] G.L. Close, T. Ashton, A. McArdle, D.P. Maclaren, The emerging role of free
radicals in delayed onset muscle soreness and contraction-induced muscle
injury, Comp Biochem Physiol A Mol Integr Physiol 142 (2005) 257–266.
[4] W.M. Abraham, Factors in delayed muscle soreness, Med Sci Sports 9 (1977)
11–20.
[5] J. Friden, P.N. Sfakianos, A.R. Hargens, Muscle soreness and intramuscular fluid
pressure: comparison between eccentric and concentric load, J Appl Physiol 61
(1986) 2175–2179.
[6] A.G. Crenshaw, L.E. Thornell, J. Friden, Intramuscular pressure, torque and
swelling for the exercise-induced sore vastus lateralis muscle, Acta Physiol
Scand 152 (1994) 265–277.
[7] J. Friden, U. Kjorell, L.E. Thornell, Delayed muscle soreness and cytoskeletal
alterations: an immunocytological study in man, Int J Sports Med 5 (1984) 15–
18.
[8] J. Friden, M. Sjostrom, B. Ekblom, A morphological study of delayed muscle
soreness, Experientia 37 (1981) 506–507.
[9] J. Friden, M. Sjostrom, B. Ekblom, Myofibrillar damage following intense
eccentric exercise in man, Int J Sports Med 4 (1983) 170–176.
[10] P. Nurenberg, C.J. Giddings, J. Stray-Gundersen, J.L. Fleckenstein, W.J. Gonyea,
R.M. Peshock, MR imaging-guided muscle biopsy for correlation of increased
signal intensity with ultrastructural change and delayed-onset muscle
soreness after exercise, Radiology 184 (1992) 865–869.
[11] J.M. Foley, R.C. Jayaraman, B.M. Prior, J.M. Pivarnik, R.A. Meyer, MR
measurements of muscle damage and adaptation after eccentric exercise, J
Appl Physiol 87 (1999) 2311–2318.
[12] M.F. Bobbert, A.P. Hollander, P.A. Huijing, Factors in delayed onset muscular
soreness of man, Med Sci Sports Exerc 18 (1986) 75–81.
[13] W.C. Byrnes, P.M. Clarkson, J.S. White, S.S. Hsieh, P.N. Frykman, R.J. Maughan,
Delayed onset muscle soreness following repeated bouts of downhill running, J
Appl Physiol 59 (1985) 710–715.
[14] P.M. Clarkson, W.C. Byrnes, K.M. McCormick, L.P. Turcotte, J.S. White, Muscle
soreness and serum creatine kinase activity following isometric, eccentric, and
concentric exercise, Int J Sports Med 7 (1986) 152–155.
[15] H. Kuipers, H.A. Keizer, F.T. Verstappen, D.L. Costill, Influence of a
prostaglandin-inhibiting drug on muscle soreness after eccentric work, Int J
Sports Med 6 (1985) 336–339.
[16] P.M. Clarkson, F.S. Apple, W.C. Byrnes, K.M. McCormick, P. Triffletti, Creatine
kinase isoforms following isometric exercise, Muscle Nerve 10 (1987) 41–44.
[17] K. Nosaka, T. Kuramata, Muscle soreness and serum enzyme activity following
consecutive drop jumps, J Sports Sci 9 (1991) 213–220.
[18] M. Vaczi, J. Tihanyi, T. Hortobagyi, L. Racz, Z. Csende, A. Costa, J. Pucsok,
Biochemical and Electromyographic Responses to Short-Term EccentricConcentric Knee Extensor Training in Humans., J Strength Cond Res 25
(2011) 922–932.
[19] K. Nosaka, M. Newton, P. Sacco, Delayed-onset muscle soreness does not
reflect the magnitude of eccentric exercise-induced muscle damage, Scand J
Med Sci Sports 12 (2002) 337–346.
[20] L.L. Smith, Acute inflammation: the underlying mechanism in delayed onset
muscle soreness?, Med Sci Sports Exerc 23 (1991) 542–551
[21] J. Bourgeois, D. MacDougall, J. MacDonald, M. Tarnopolsky, Naproxen does not
alter indices of muscle damage in resistance-exercise trained men, Med Sci
Sports Exerc 31 (1999) 4–9.
[22] G.L. Close, T. Ashton, T. Cable, D. Doran, D.P. MacLaren, Eccentric exercise,
isokinetic muscle torque and delayed onset muscle soreness: the role of
reactive oxygen species., Eur J Appl Physiol 91 (2004) 615–621.
[23] S.K. Powers, W.B. Nelson, M.B. Hudson, Exercise-induced oxidative stress in
humans: Cause and consequences. Free Radic Biol Med 51 (2011) 942–950.
[24] H. Bo, N. Jiang, G. Ma, J. Qu, G. Zhang, D. Cao, L. Wen, S. Liu, L.L. Ji, Y. Zhang,
Regulation of mitochondrial uncoupling respiration during exercise in rat
heart: role of reactive oxygen species (ROS) and uncoupling protein 2, Free
Radic Biol Med 44 (2008) 1373–1381.
[25] Z. Radak, M. Sasvari, C. Nyakas, A.W. Taylor, H. Ohno, H. Nakamoto, S. Goto,
Regular training modulates the accumulation of reactive carbonyl derivatives
in mitochondrial and cytosolic fractions of rat skeletal muscle, Arch Biochem
Biophys 383 (2000) 114–118.
[26] G. Camus, G. Deby-Dupont, J. Duchateau, C. Deby, J. Pincemail, M. Lamy, Are
similar inflammatory factors involved in strenuous exercise and sepsis?,
Intensive Care Med 20 (1994) 602–610
[27] Z. Radak, J. Pucsok, S. Mecseki, T. Csont, P. Ferdinandy, Muscle sorenessinduced reduction in force generation is accompanied by increased nitric oxide
content and DNA damage in human skeletal muscle, Free Radic Biol Med 26
(1999) 1059–1063.
[28] R.J. Morrison, C.C. Miller 3rd, M.B. Reid, Nitric oxide effects on force-velocity
characteristics of the rat diaphragm, Comp Biochem Physiol A Mol Integr
Physiol 119 (1998) 203–209.
[29] J.M. Percival, K.N. Anderson, P. Huang, M.E. Adams, S.C. Froehner, Golgi and
sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue
and vasoconstriction in exercising mouse skeletal muscle, J Clin Invest 120
(2010) 816–826.
[30] M.B. Reid, L. Kobzik, D.S. Bredt, J.S. Stamler, Nitric oxide modulates excitationcontraction coupling in the diaphragm, Comp Biochem Physiol A Mol Integr
Physiol 119 (1998) 211–218.
[31] S. Pouvreau, V. Jacquemond, Nitric oxide synthase inhibition affects
sarcoplasmic reticulum Ca2+ release in skeletal muscle fibres from mouse, J
Physiol 567 (2005) 815–828.
[32] J.S. Lee, Y. Zhang, J.Y. Ro, Involvement of neuronal, inducible and endothelial
nitric oxide synthases in capsaicin-induced muscle hypersensitivity, Eur J Pain
13 (2009) 924–928.
[33] J. Ellrich, A. Fischer, J.M. Gilsbach, A. Makowska, P. Spangenberg, Inhibition of
nitric oxide synthases prevents and reverses alpha, beta-meATP-induced neck
muscle nociception in mice, Cephalalgia 30 (2010) 1225–1232.
Z. Radak et al. / Nitric Oxide 26 (2012) 89–94
[34] L.I. Filippin, M.J. Cuevas, E. Lima, N.P. Marroni, J. Gonzalez-Gallego, R.M. Xavier,
Nitric oxide regulates the repair of injured skeletal muscle, Nitric oxide 24
(2011) 43–49.
[35] J.E. Anderson, A role for nitric oxide in muscle repair: nitric oxide-mediated
activation of muscle satellite cells, Mol Biol Cell 11 (2000) 1859–1874.
[36] J.R. Leiter, J.E. Anderson, Satellite cells are increasingly refractory to activation
by nitric oxide and stretch in aged mouse-muscle cultures, Int J Biochem Cell
Biol 42 (2010) 132–136.
[37] P.M. Tiidus, C.D. Ianuzzo, Effects of intensity and duration of muscular exercise
on delayed soreness and serum enzyme activities, Med Sci Sports Exerc 15
(1983) 461–465.
[38] A. Chatzinikolaou, I.G. Fatouros, V. Gourgoulis, A. Avloniti, A.Z. Jamurtas, M.G.
Nikolaidis, I. Douroudos, Y. Michailidis, A. Beneka, P. Malliou, T. Tofas, I.
Georgiadis, D. Mandalidis, K. Taxildaris, Time course of changes in
performance and inflammatory responses after acute plyometric exercise, J
Strength Cond Res 24 (2010) 1389–1398.
[39] A. Skurvydas, M. Brazaitis, S. Kamandulis, Prolonged muscle damage depends
on force variability, Int J Sports Med 31 (2010) 77–81.
[40] L. Kobzik, M.B. Reid, D.S. Bredt, J.S. Stamler, Nitric oxide in skeletal muscle,
Nature 372 (1994) 546–548.
[41] J.M. Percival, K.N. Anderson, P. Gregorevic, J.S. Chamberlain, S.C. Froehner,
Functional deficits in nNOSmu-deficient skeletal muscle: myopathy in nNOS
knockout mice, PLoS One 3 (2008) e3387.
[42] R.J. Morrison, C.C. Miller 3rd, M.B. Reid, Nitric oxide effects on shortening
velocity and power production in the rat diaphragm, J Appl Physiol 80 (1996)
1065–1069.
[43] W.J. Chang, S.T. Iannaccone, K.S. Lau, B.S. Masters, T.J. McCabe, K. McMillan,
R.C. Padre, M.J. Spencer, J.G. Tidball, J.T. Stull, Neuronal nitric oxide synthase
and dystrophin-deficient muscular dystrophy, Proc Natl Acad Sci U S A 93
(1996) 9142–9147.
[44] P.V. Finocchietto, M.C. Franco, S. Holod, A.S. Gonzalez, D.P. Converso, V.G.
Arciuch, M.P. Serra, J.J. Poderoso, M.C. Carreras, Mitochondrial nitric oxide
synthase: a masterpiece of metabolic adaptation, cell growth, transformation,
and death, Exp Biol Med (Maywood) 234 (2009) 1020–1028.
[45] J.E. Sellman, K.C. DeRuisseau, J.L. Betters, V.A. Lira, Q.A. Soltow, J.T. Selsby, D.S.
Criswell, In vivo inhibition of nitric oxide synthase impairs upregulation of
contractile protein mRNA in overloaded plantaris muscle, J Appl Physiol 100
(2006) 258–265.
[46] L. Nogueira, C. Figueiredo-Freitas, G. Casimiro-Lopes, M.H. Magdesian, J.
Assreuy, M.M. Sorenson, Myosin is reversibly inhibited by S-nitrosylation,
Biochem J 424 (2009) 221–231.
[47] Y.M. Kobayashi, E.P. Rader, R.W. Crawford, N.K. Iyengar, D.R. Thedens, J.A.
Faulkner, S.V. Parikh, R.M. Weiss, J.S. Chamberlain, S.A. Moore, K.P. Campbell,
Sarcolemma-localized nNOS is required to maintain activity after mild
exercise, Nature 456 (2008) 511–515.
[48] Z. Radak, H.Y. Chung, H. Naito, R. Takahashi, K.J. Jung, H.J. Kim, S. Goto, Ageassociated increase in oxidative stress and nuclear factor kappaB activation are
attenuated in rat liver by regular exercise, FASEB J 18 (2004) 749–750.
[49] E. Lima-Cabello, M.J. Cuevas, N. Garatachea, M. Baldini, M. Almar, J. GonzalezGallego, Eccentric exercise induces nitric oxide synthase expression through
nuclear factor-kappaB modulation in rat skeletal muscle, J Appl Physiol 108
(2010) 575–583.
[50] A. Steensberg, C. Keller, T. Hillig, C. Frosig, J.F. Wojtaszewski, B.K. Pedersen, H.
Pilegaard, M. Sander, Nitric oxide production is a proximal signaling event
controlling exercise-induced mRNA expression in human skeletal muscle,
FASEB J 21 (2007) 2683–2694.
[51] V. Calabrese, C. Cornelius, E. Rizzarelli, J.B. Owen, A.T. Dinkova-Kostova, D.A.
Butterfield, Nitric oxide in cell survival: a janus molecule, Antioxid Redox
Signal 11 (2009) 2717–2739.
[52] J.T. Hancock, The role of redox mechanisms in cell signalling, Mol Biotechnol
43 (2009) 162–166.
[53] J.S. Stamler, G. Meissner, Physiology of nitric oxide in skeletal muscle, Physiol
Rev 81 (2001) 209–237.
[54] G. Marechal, G. Beckers-Bleukx, Effect of nitric oxide on the maximal velocity
of shortening of a mouse skeletal muscle, Pflugers Arch 436 (1998) 906–913.
[55] M.B. Reid, Role of nitric oxide in skeletal muscle: synthesis, distribution and
functional importance, Acta Physiol Scand 162 (1998) 401–409.
[56] J.P. Folland, H. Maas, D.A. Jones, The influence of nitric oxide on in vivo human
skeletal muscle properties, Acta Physiol Scand 169 (2000) 141–148.
[57] M.B. Reid, W.J. Durham, Generation of reactive oxygen and nitrogen species in
contracting skeletal muscle: potential impact on aging, Ann N Y Acad Sci 959
(2002) 108–116.
[58] Z. Radak, H.Y. Chung, S. Goto, Exercise and hormesis: oxidative stress-related
adaptation for successful aging, Biogerontology 6 (2005) 71–75.
[59] Z. Radak, H.Y. Chung, S. Goto, Systemic adaptation to oxidative challenge
induced by regular exercise, Free Radic Biol Med 44 (2008) 153–159.
[60] M.P. Mattson, Hormesis and disease resistance. activation of cellular stress
response pathways, Hum Exp Toxicol 27 (2008) 155–162.
[61] V. Calabrese, C. Cornelius, A.T. Dinkova-Kostova, E.J. Calabrese, M.P. Mattson,
Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets
for therapeutic intervention in neurodegenerative disorders, Antioxid Redox
Signal 13 (2010) 1763–1811.
[62] J. Boczkowski, S. Lanone, D. Ungureanu-Longrois, G. Danialou, T. Fournier, M.
Aubier, Induction of diaphragmatic nitric oxide synthase after endotoxin
administration in rats: role on diaphragmatic contractile dysfunction, J Clin
Invest 98 (1996) 1550–1559.
93
[63] F.H. Andrade, M.B. Reid, D.G. Allen, H. Westerblad, Effect of nitric oxide on
single skeletal muscle fibres from the mouse, J Physiol 509 (Pt 2) (1998) 577–
586.
[64] S. Galler, K. Hilber, A. Gobesberger, Effects of nitric oxide on force-generating
proteins of skeletal muscle, Pflugers Arch 434 (1997) 242–245.
[65] L.M. Heunks, M.J. Cody, P.C. Geiger, P.N. Dekhuijzen, G.C. Sieck, Nitric oxide
impairs Ca2+ activation and slows cross-bridge cycling kinetics in skeletal
muscle, J Appl Physiol 91 (2001) 2233–2239.
[66] J.M. Chesnais, R. Fischmeister, P.F. Mery, Positive and negative inotropic effects
of NO donors in atrial and ventricular fibres of the frog heart, J Physiol 518
(1999) 449–461.
[67] A.C. Cabral de Oliveira, A.C. Perez, J.G. Prieto, I.D. Duarte, A.I. Alvarez,
Protection of Panax ginseng in injured muscles after eccentric exercise, J
Ethnopharmacol 97 (2005) 211–214.
[68] R. Jimenez-Jimenez, M.J. Cuevas, M. Almar, E. Lima, D. Garcia-Lopez, J.A. De
Paz, J. Gonzalez-Gallego, Eccentric training impairs NF-kappaB activation and
over-expression of inflammation-related genes induced by acute eccentric
exercise in the elderly, Mech Ageing Dev 129 (2008) 313–321.
[69] J. Chiang, Y.C. Shen, Y.H. Wang, Y.C. Hou, C.C. Chen, J.F. Liao, M.C. Yu, C.W. Juan,
K.T. Liou, Honokiol protects rats against eccentric exercise-induced skeletal
muscle damage by inhibiting NF-kappaB induced oxidative stress and
inflammation, Eur J Pharmacol 610 (2009) 119–127.
[70] A. Zembron-Lacny, M. Naczk, M. Gajewski, J. Ostapiuk-Karolczuk, H.
Dziewiecka, A. Kasperska, K. Szyszka, Changes of muscle-derived cytokines
in relation to thiol redox status and reactive oxygen and nitrogen species,
Physiol Res 59 (2010) 945–951.
[71] T. Pullinen, A. Mero, P. Huttunen, A. Pakarinen, P.V. Komi, Resistance exerciseinduced hormonal response under the influence of delayed onset muscle
soreness in men and boys, Scand J Med Sci Sports 21 (2011) 184–194.
[72] T.L. Rice, I. Chantler, L.C. Loram, Neutralisation of muscle tumour necrosis
factor alpha does not attenuate exercise-induced muscle pain but does
improve muscle strength in healthy male volunteers, Br J Sports Med 42
(2008) 758–762.
[73] M.P. Miles, P.M. Clarkson, Exercise-induced muscle pain, soreness, and cramps,
J Sports Med Phys Fitness 34 (1994) 203–216.
[74] K. Itoh, K. Kawakita, Effect of indomethacin on the development of eccentric
exercise-induced localized sensitive region in the fascia of the rabbit, Jpn J
Physiol 52 (2002) 173–180.
[75] P. Barlas, J.A. Craig, J. Robinson, D.M. Walsh, G.D. Baxter, J.M. Allen, Managing
delayed-onset muscle soreness: lack of effect of selected oral systemic
analgesics, Arch Phys Med Rehabil 81 (2000) 966–972.
[76] L. Tegeder, J. Zimmermann, S.T. Meller, G. Geisslinger, Release of algesic
substances in human experimental muscle pain, Inflamm Res 51 (2002) 393–
402.
[77] T.B. Kelso, C.R. Shear, S.R. Max, Enzymes of glutamine metabolism in
inflammation associated with skeletal muscle hypertrophy, Am J Physiol 257
(1989) E885–E894.
[78] I. Tegeder, S. Meier, M. Burian, H. Schmidt, G. Geisslinger, J. Lotsch, Peripheral
opioid analgesia in experimental human pain models, Brain 126 (2003) 1092–
1102.
[79] S. Murase, E. Terazawa, F. Queme, H. Ota, T. Matsuda, K. Hirate, Y. Kozaki, K.
Katanosaka, T. Taguchi, H. Urai, K. Mizumura, Bradykinin and nerve growth
factor play pivotal roles in muscular mechanical hyperalgesia after exercise
(delayed-onset muscle soreness), J Neurosci 30 (2010) 3752–3761.
[80] C.J. Liu, and N.K. Latham, Progressive resistance strength training for
improving physical function in older adults. Cochrane Database Syst Rev
(2009) CD002759.
[81] G. Howatson, K.a. Van Someren, The prevention and treatment of exerciseinduced muscle damage, Sports Med 38 (2008) 483–503.
[82] E.C. Rubini, A.L. Costa, P.S. Gomes, The effects of stretching on strength
performance, Sports Med 37 (2007) 213–224.
[83] A. Barnett, Using recovery modalities between training sessions in elite
athletes: does it help?, Sports Med 36 (2006) 781–796
[84] P. Weerapong, P.A. Hume, G.S. Kolt, The mechanisms of massage and effects on
performance, muscle recovery and injury prevention, Sports Med 35 (2005)
235–256.
[85] U. Proske, T.J. Allen, Damage to skeletal muscle from eccentric exercise, Exerc
Sport Sci Rev 33 (2005) 98–104.
[86] A. Pisconti, S. Brunelli, M. Di Padova, C. De Palma, D. Deponti, S. Baesso, V.
Sartorelli, G. Cossu, E. Clementi, Follistatin induction by nitric oxide through
cyclic GMP: a tightly regulated signaling pathway that controls myoblast
fusion, J Cell Biol 172 (2006) 233–244.
[87] Z.L. Szomor, R.C. Appleyard, G.A. Murrell, Overexpression of nitric oxide
synthases in tendon overuse, J Orthop Res 24 (2006) 80–86.
[88] U. Kerkweg, D. Schmitz, H. De Groot, Screening for the formation of
reactive oxygen species and of NO in muscle tissue and remote organs
upon mechanical trauma to the mouse hind limb, Eur Surg Res 38 (2006)
83–89.
[89] M.X. Wang, D.F. Murrell, C. Szabo, R.F. Warren, M. Sarris, G.A. Murrell, Nitric
oxide in skeletal muscle: inhibition of nitric oxide synthase inhibits walking
speed in rats, Nitric oxide 5 (2001) 219–232.
[90] B. Hoier, N. Rufener, J. Bojsen-Moller, J. Bangsbo, Y. Hellsten, The effect of
passive movement training on angiogenic factors and capillary growth in
human skeletal muscle, J Physiol 588 (2010) 3833–3845.
[91] M.V. Negrao, C.R. Alves, G.B. Alves, A.C. Pereira, R.G. Dias, M.C. Laterza, G.F.
Mota, E.M. Oliveira, V. Bassaneze, J.E. Krieger, C.E. Negrao, M.U. Rondon,
94
Z. Radak et al. / Nitric Oxide 26 (2012) 89–94
Exercise training improves muscle vasodilatation in individuals with T786C
polymorphism of endothelial nitric oxide synthase gene, Physiol Genomics
42A (2010) 71–77.
[92] R.S. Lee-Young, J.E. Ayala, C.F. Hunley, F.D. James, D.P. Bracy, L. Kang, D.H.
Wasserman, Endothelial nitric oxide synthase is central to skeletal muscle
metabolic regulation and enzymatic signaling during exercise in vivo, Am J
Physiol Regul Integr Comp Physiol 298 (2010) R1399–R1408.
[93] E. Carmeli, R. Beiker, M. Maor, E. Kodesh, Increased iNOS, MMP-2, and HSP-72
in skeletal muscle following high-intensity exercise training, J Basic Clin
Physiol Pharmacol 21 (2010) 127–146.
[94] K.L. McIver, C. Evans, R.M. Kraus, L. Ispas, V.M. Sciotti, R.C. Hickner, NOmediated alterations in skeletal muscle nutritive blood flow and lactate
metabolism in fibromyalgia, Pain 120 (2006) 161–169.
[95] J.D. Archer, C.C. Vargas, J.E. Anderson, Persistent and improved functional gain
in mdx dystrophic mice after treatment with L-arginine and deflazacort, FASEB
J 20 (2006) 738–740.
[96] N. Lomonosova Iu, A.V. Zhelezniakova, A.E. Bugrova, A.V. Zhiriakova, G.R.
Kalamkarov, T.L. Nemirovskaia, Protective effect of nitric oxide on cytoskeletal
proteins in skeletal muscles under eccentric exercise, Biofizika 54 (2009) 515–
521.