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Journal of Sport and Health Science xx (2015) 1e11
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Review

Exercise-induced rhabdomyolysis mechanisms and prevention:

A literature review
Jooyoung Kim a,1, Joohyung Lee a,1, Sojung Kim b, Ho Young Ryu c, Kwang Suk Cha c,
Dong Jun Sung c,*
a
Health and Rehabilitation Major, College of Physical Education, Kookmin University, Seoul 136-702, Republic of Korea
b
Department of Physical Education, Global Campus, Kyung Hee University, Suwon 446-701, Republic of Korea
c
Division of Sport Science, College of Science and Technology, Konkuk University, Choong-Ju 380-702, Republic of Korea
Received 28 June 2014; revised 26 October 2014; accepted 26 January 2015

Abstract

Exercise-induced rhabdomyolysis (exRML), a pathophysiological condition of skeletal muscle cell damage that may cause acute renal failure
and in some cases death. Increased Ca2þ level in cells along with functional degradation of cell signaling system and cell matrix have been
suggested as the major pathological mechanisms associated with exRML. The onset of exRML may be exhibited in athletes as well as in general
population. Previous studies have reported that possible causes of exRML were associated with excessive eccentric contractions in high tem-
perature, abnormal electrolytes balance, and nutritional deficiencies possible genetic defects. However, the underlying mechanisms of exRML
have not been clearly established among health professionals or sports medicine personnel. Therefore, we reviewed the possible mechanisms and
correlated prevention of exRML, while providing useful and practical information for the athlete and general exercising population.
Copyright Ó 2015, Shanghai University of Sport. Production and hosting by Elsevier B.V. All rights reserved.

Keywords: Acute renal failure; Calcium (Ca2þ); Creatine kinase; Myoglobin (Mb); Rhabdomyolysis

1. Introduction dysfunction, compartment syndrome, heart failure, arrhythmias,

electrolyte imbalance, and in severe cases also to death.2,3
The number of people participating in regular as well as exRML can occur via highly intense and prolonged exercise
organized exercise programs has been continuously increasing. or due to sudden and excessive contraction of skeletal muscles.
The increase in popularity of physical activity and exercise may Symptoms of exRML are similar to those of delayed onset
be due to positive effects on physical and mental health. How- muscle soreness that can be easily overlooked.4 Despite its
ever, excessive or intense exercise beyond the extent of personal importance, people who participate in exercise may not be aware
or physical limits may induce various types of musculoskeletal of exRML. Therefore, the purposes of this review are to provide
damage, including exercise-induced rhabdomyolysis (exRML), exercising population with information about the possible
a pathophysiological condition of skeletal muscle cell damage.1 mechanisms of exRML and offer preventive strategies to avoid
exRML may be manifested by an increase in creatine kinase exRML based on results of previously conducted studies.
(CK) or myoglobin (Mb), seeping into the blood stream through
damaged cell membrane as results of excessive or intense ex-
ercise.1 exRML may lead to acute renal failure, liver 2. Pathophysiology of exRML

2.1. Role of calcium in the pathogenesis of exRML

* Corresponding author.
E-mail address: [email protected] (D.J. Sung)
Peer review under responsibility of Shanghai University of Sport. Ca2þ has been suggested as an important factor in the
1
Jooyoung Kim and Joohyung Lee contributed equally to this work. pathogenesis of exRML (Fig. 1). Numerous studies5,6 have

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2 J. Kim et al.

Fig. 1. The pathophysiological mechanism of rhabdomyolysis focusing on the increase of Ca2þ. A: Deficiency of ATP due to high intensity exercise and continuous
muscle contraction could induce the dysfunction of Naþ-Kþ ATPase, causing subsequent activation of reverse mode Naþ-Ca2þ exchanger; B: Depolarization of
sarcolemma and T-tubule by an action potential could activate dihydropyridine receptor and promote the secretion of Ca2þ via ryanodine receptor in sarcoplasmic
reticulum; C: The increase of Ca2þ due to Ca2þdiffused by the rupture of sarcolemma from trauma; D: The entry of store-operated Ca2þ through transient receptor
potential channel 1 or transient receptor potential channel 3 with reduced levels of Ca2þ in the sarcoplasmic reticulum; E: The secretion of Ca2þ (Ca2þ-induced
Ca2þ release) from sarcoplasmic reticulum in accordance with the increase of Ca2þ in sarcoplasm. / represents activation; represents inhibition,
represents candidate mechanisms in the regulation of Ca2þ. ATP ¼ adenosine triphosphate; DHPR ¼ dihydropyridine receptor; PLA2 ¼ phospholipase A2;
ROS ¼ reactive oxygen species; SR ¼ sarcoplasmic reticulum; NCXR ¼ Naþ/Ca2þ exchanger; SOCE ¼ store-operated Ca2þ entry; CICR ¼ Ca2þ-induced
calcium release; TRPC ¼ transient receptor potential cation channels.

shown increased levels of Ca2þ in cells of exRML patients. could cause dysfunction of the Naþ-Kþ ATPase,14 resulting in
The concentration of Ca2þ should remain at nano-molar levels an increased level of Naþ in the cells.17 Normal function of
under resting conditions. Ca2þ would increase to mille-molar Naþ-Kþ would activate Naþ-Ca2þ exchanger in the forward
levels through cell activation and muscle contraction during mode (Ca2þ extrusion). However, due to the dysfunction of
exercise.7 Ryanodine receptors in the sarcoplasmic reticulum, Naþ-Kþ ATPase, increased level of Naþ in cells would acti-
dihydropyridine receptors (i.e., voltage-gated L-type Ca2þ vate the reverse mode of Naþ-Ca2þ exchanger (Ca2þ influx),
channels), and Ca2þ pump are the three major pathways thereby increasing the level of Ca2þ in the cells.18 During the
controlling the Ca2þ in skeletal muscle cells.8e10 Transient cycle of contraction and relaxation of skeletal muscle, Ca2þ in
receptor potential channel (non-selective cation channel),11 the sarcoplasm repeatedly gain sentry through the Ca2þ pump
Ca2þ-induced Ca2þ release,12 and Naþ-Ca2þ exchanger13 in the membrane of sarcoplasmic reticulum.7 Normal function
contribute to the control of Ca2þ. Increased Ca2þ concentra- of the Ca2þ pump requires the hydrolysis of ATP.19,20 If the
tion has been reported in the sarcoplasm of exRML patients6 amount of ATP is insufficient, the Ca2þ pump would result in
with deficiency or depletion of adenosine triphosphate (ATP) abnormal function. Zhang21 suggested that dysfunction of ion
due to intensity of exercise. ATP is continuously synthesized regulation proteins as, a Naþ-Kþ ATPase, Naþ-Ca2þ
during exercise. When the amount of ATP is severely depleted, exchanger, and Ca2þ pump in skeletal muscle may be strongly
ATP-dependent ion transporter may be affected.14 ATP- related to rhabdomyolysis (RML).
dependent transporters of skeletal muscle cells are Naþ-Kþ Ca2þ-induced Ca2þ release has been detected earlier than
ATPase15 and Ca2þ ATPase16 ion transporters. When skeletal inositol 1,4,5-triphosphate-induced Ca2þ release for the reser-
muscle cells are excited, Naþ influx through the voltage-gated vation or mobilization of Ca2þ in the sarcoplasm.12 Ca2þ-
Naþ channel creates an action potential, resulting in similar induced Ca2þ release is not the primary Ca2þ control mecha-
amounts of Kþ efflux through the Kþ channel. The movement nism in the skeletal muscles. It is achieved via proteineprotein
of these ions strengthens the capacity of Naþ-Kþ ATPase to interaction of voltage sensor dihydropyridine receptor of the
readjust the distribution of ions in the sarcoplasm.15 The efflux T-tubule with the Ca2þ release channel ryanodine receptor of the
of Naþ and the influx of Kþ become ATP-dependent and move sarcoplasmic reticulum membrane.22,23 According to the Ca2þ-
in the opposite direction of the concentration gradient. If the induced Ca2þ release mechanism, membrane depolarization
amount of ATP is deficient or insufficient, the activity of Naþ- caused by the action potential increases the levels of Ca2þ in the
Kþ ATPase would be reduced. Decreased amount of ATP sarcoplasm, thus releasing Ca2þ from the Ca2þ store

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Exercise-induced rhabdomyolysis 3

(sarcoplasmic reticulum). Ryanodine receptor and inositol pathogenesis of an acute renal failure originating from exRML
1,4,5-triphosphate are both associated with Ca2þ-induced has not been clearly recognized, previous studies have sug-
Ca2þ release.12 Due to consistent contraction of skeletal mus- gested an association between increased Mb and Kþ ion and
cles, increased level of Ca2þ in the sarcoplasm may activate uric acid affecting the glomerulus of kidneys.40 Particularly
Ca2þ-induced Ca2þ release, which may have asynergistic effect Mb could easily permeate the glomerular membrane and
and subsequently increase the level of Ca2þ even more. Tran- subsequently increase the amount of Mb as results of
sient receptor potential channels are non-selective cation continued muscle damage.44
channels permeable to Naþ and Ca2þ.7 In skeletal muscles, The mechanism of exRML-induced acute renal failure may
transient receptor potential canonical (TRPC) types 1 and 3 be referred to vasoconstriction. Necrosis in muscular tissues
have been identified, with TRPC3 being reported to interact may create additional space for increased accumulation of
with ryanodine receptor.24,25 The activation of store-operated intravascular fluid and generate hypovolemia,45,46 that may
Ca2þ entry by TRPC1/3 with a Ca2þ deficiency of the sarco- activate sympathetic tone and renin angiotensinealdosterone
plasmic reticulum due to ryanodine receptor or inositol 1,4,5- system, inducing vasoconstriction and activate additional
triphosphate activation may increase the levels of Ca2þ in the vasoactivator (e.g., endothelin 1, vasopressin) that are known
sarcoplasm.26,27 The malignant hyperthermia is characterized to suppress vasodilation induced by protaglandins.47e49
by an increase in RML28 and store operated cation channels Damage to muscles promotes extrication of endotoxins and
involving TRPC3 accelerated activation by malignant hyper- cytokines into systemic circulation and thus promoting vaso-
thermia.29 This leads to increasing intracellular Ca2þ and in- constriction.50,51 Mb also plays an important role in decreasing
dicates that store operated cation channels and/or TRPC3 is nitric oxide and vasodilation.52,53 Under these conditions, the
contributing to the development of RML. creation of ATP would be reduced resulting in vasoconstric-
Increased level of Ca2þ has been reported to have influence tion, renal ischemia, and reduction in oxygen.45
on the activation of proteases and phospholipase A2.30,31 Cast formation is a contributor in the development of
These responses are strongly associated with damage or exRML-induced acute renal failure.37,44 Deficit in ATP may
decomposition of phospholipids of the cell membrane,32 cause necrosis of epithelial cells, accumulation of dead cells in
which could induce damage to the cell membrane and the tubular lumen, resulting in the precipitation of Mb and
reveal toxicity caused by several types of molecular efflux.5 formation of casts.47,54 Mb is filtrated at the renal glomeruli.55
In addition, the increase in Ca2þ concentration in the mito- The increase in Mb in pre-urine is accompanied by acidifi-
chondria due to chemical gradient of Ca2þ between the cation, and thus, increasing the accumulation of Mb and Mb
sarcoplasm and mitochondria may be another plausible cast formation in the distal convoluted tubules.56 The accu-
mechanism of damage.20,33 This reaction could promote the mulation of Mb induces constriction of blood vessels and
creation of reactive oxygen species (ROS) in the mitochon- initiates ischemia, reducing the function of renal tubules in
dria,34 which could damage proteins, lipids, and nucleic filtering metabolites and waste products.53 The accumulation
acids.35,36 This type of damage could reduce the synthesis of of Mb also creates ROS and induces lipid peroxidation that
cell membrane, proteins, and/or ATP.34 The increase of Ca2þ produces cell membrane and blood vessels in kidneys causing
in the sarcoplasm and mitochondria may amplify the temporary or chronic impairment of normal kidney
signaling of apoptosis and promoting cell death.37e39 function.57,58
Furthermore, rupture of muscular cell membrane caused by
injury, toxicity, or exercise may induce the influx of Ca2þ into 2.3. Primary factors
cells due to concentration gradient, contributing to the
elevation of Ca2þ concentration in the sarcoplasm.20,37 During exercise, factors that may cause exRML include the
Therefore, the increase in Ca2þ in cells may induce exRML exercise experience of participants, level of physical fitness,
by creating energy, while controlling the cell signaling the intensity, duration, and types of exercises. Line and Rust59
pathway system through interactions that may cause cell reported that exRML tends to appear more often in people
death. with little or no exercise experience or in athletes who are less
trained than others. In addition, a positive relationship was
2.2. Role of myoglobin in exRML-induced acute renal found between exRML and soldiers performing sedentary
failure duties compared to trained soldiers.60 Paul et al.61 reported
that highly experienced weight-lifters exhibited relatively
Among complications of exRML, acute renal failure has lower levels of CK and Mb than less experienced weight-
shown the greatest incidence rate increase.40,41 Park et al.42 lifters.
reported that 10%e30% of exRML patients may have Other important factors in exRML are the intensity and
accompanying acute renal failure, making exRML a clinically duration of exercises. Clarkson62 found that the typical onset
important condition due to strong correlation between acute of exRML was extreme muscle soreness and brown colored
renal failure and death. Acute renal failure from exRML may urine in 12-year-old boys who performed squat jumps
be caused by the delay of treatment due to failure of recog- 250e500 times. Moeckel-Cole and Clarkson63 also reported
nizing severe muscle damage and the presence of renal dis- the onset of exRML in college soccer players who conducted
eases or age-related biological decline.43 While the highly intense weight training and performed 300 squat jumps.
Please cite this article in press as: Kim J, et al., Exercise-induced rhabdomyolysis mechanisms and prevention: A literature review, Journal of Sport and Health
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4 J. Kim et al.

Table 1
Case reports of exercise-induced rhabdomyolysis.
Researcher Subject Exercise mode Symptom Complication
43
Park et al. 20 years male Scuba diving Vomiting, CK 12,054 U/L, Mb 3000 mg/mL ARF
Clarkson62 12 years male Weight training Brown urine, CK 92,115 U/L, AST 1520 U/L None
Moeckel-Coke 18 years male Weight training Brown urine, CK 130,899 U/L None
and Clarkson63
Morrison143 27 years female Weight training Muscle pain, CK 16,000 U/L, LDH 9349 U/L, AST 976 U/L Compartment
syndrome
Goubier et al.144 30 years male Weight training Sever muscle pain, muscle edema, CK 113,260 U/L, LDH 790 U/L None
Kim et al.145 28 years male Weight training Edema, Muscle pain, CK 52,240 U/L, LDH 2277 U/L Hepatitis
Gagliano et al.146 30 years male Bodybuilding CK 70,920 U/L, LDH 4981 U/L, Mb 1702 U/L ARF
Inklebarger et al.85 63 years male Stationary bike Sever muscle pain, Brown urine, CK 38,120 U/L, Mb 5330 U/L None
Thoenes147 17 years male Stationary bike Brown urine, sever muscle pain, CK is not suggested. None
Karre and Gujral148 24 years male Low intensity Joint pain, brown urine, CK 214,356 U/L, Mb 1347 mg/mL None
exercise
MacDonald et al.149 26.7 years (19e40 years), Weight training Muscle aches, some subjects had hematuria and proteinuria, Unknown
n ¼ 17 CK 1800e220,000 U/L
Pierson et al.150 25 years male Weight training CK 31,950 U/L, Mb 50 ng/mL Not present
Summachiwakij 33 years male Non-strenuous Brown urine, AST 993 U/L, ALT 228 U/L, LDH 2330 U/L, Not present
and Sachmechi151 with Grave’s disease exercise CK 98,407 U/L
Abbreviations: CK ¼ creatine kinase; Mb ¼ myoglobin; LDH ¼ lactate dehydrogenase; AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase;
ARF ¼ acute renal failure.

In addition, Russo and Bass64 reported exRML in a 17-year- were reported to have more exRML compared to general
old male basketball player who had CK level of 241,026 U/L population.68 Soldiers who undergo special force physical
after completing 800 sit-ups, 400 push-ups, and a 3.2-km run. training or ranger activities with long distance marching in hot
The determinations of exRML manifested from other sources outdoor environments69,70 and athletes who are exposed to
are summarized in Table 1. high heat in outdoor environments when participating in long
The type of exercise is also considered an important factor activities for hours, such as marathon or triathlon, might be
in the development of exRML. It has been found that eccentric particularly susceptible to exRML.71,72
contraction of muscles may cause exRML more often than
concentric contraction.40,65,66 Kinematic factors of tension, 2.4.2. Electrolyte imbalance
changes in the length of eccentric contraction of the muscle, Aizawa et al.73 reported expression of exRML in a 22-year-
and attenuation of the bonding between contractile proteins old male soldier who presented with fever, retching, and fa-
have been suggested to explain these findings.57,67 According tigue after highly intense physical training for 3 days. They
to a previous study,66 muscle soreness along with the suggested that electrolyte imbalance (hypokalemia or hypo-
appearance of CK or Mb in the blood appeared often in the natremia) may have produced these symptoms.73 Kþ ion
blood after exercises containing an excessive component of generally would increase blood flow to the contracting mus-
eccentric contractions. Prolonged and high intensity exercises cles during exercise. However, in the case of excessive exer-
(e.g., marathon, triathlon, soccer, body-building, or Crossfit) cise in high temperatures, the body may compromise its
have been reported to activate exRML.45,58,59 homeostasis to control body heat. As a result, potential hy-
pokalemia may be generated due to sweating, therefore
2.4. Secondary factors reducing the blood flow to the muscles and induced exRML.74
According to Park et al.42 hypokalemia may lead to exRML by
2.4.1. Hot environments changing voltage of safety film on the cell membrane by
Exertional heat stroke syndrome induced fever and en- impeding the synthesis of muscle energy substrates such as
cephalopathy (delirium, seizures, and coma) as well as the glycogen. Naþ is closely associated with muscle contraction
muscle weakness could lead to exRML.37 A hyperthermal and Naþ-Kþ ATPase may be markedly reduced in a high
environments may increase body temperature above 42 C temperature environment, resulting in exRML.75 It has been
accompanied by liquation of the lipids constituting the muscle reported that exRML was induced in body builders who
cell membrane disturbance by suppressing the process of in- avoided Naþ and water intake to generate a contrasting con-
ternal oxidative phosphorylation or inducing protein denatur- tour of muscles, which affected the electrolyte imbalance.76
ation in the mitochondria, resulting in hemodynamic changes
and subordinate activation of inflammatory cytokines that may 2.4.3. Sex
be responsible for exRML.41 Excessive exercise in high hu- The incidence of exRML in males has been reported to be
midity and temperature has been reported to be the most se- higher compared to females.72,77,78 A female group was re-
vere condition that induces exRML.44 Soldiers and athletes ported to have less increase in CK level than the male group.79
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Exercise-induced rhabdomyolysis 5

In menopausal women, the secretion of CK and lactate de- recommended.89 Such excessive intake may cause imbalance
hydrogenase (LDH) were diminished in the group taking es- in body water, triggering muscle cramps or dehydration, which
trogen hormone supplement.80 The incidence of exRML was may be the root cause of renal failure or exRML. A male
reported to be lower in female athletes than in male athletes.77 weight lifter was reported to have renal failure and compart-
A report from the U.S. Centers for Disease Control and Pre- ment syndrome including exRML after taking high doses of
vention also reported that exRML was observed in 32 men, but creatine supplement.91 A case of recurrence of steroid-
not in 84 women among 16,506 fire fighters who participated responsive nephrotic syndrome along with reduced creatinine
in a physical strength examination.81 In an epidemiological clearance rate caused by the intake of creatine supplement was
investigation of exRML in high school students, male students also reported.92
were found to have more cases of exRML than female stu- The excessive use of medication for medical or entertain-
dents.66 At 24 h post marathon, the level of CK in the male ment purposes can also cause RML. Excessive exercise while
group was 3322 IU/L that was significantly higher than in the taking drugs for medical reasons may lead to potentially
female group constituting 946 IU/L.82 Therefore, males are adverse drug reactions. A rare case of induced RML by statin
more vulnerable to exRML than females. It was reported that (medication administered for patients to control hyperlipid-
estrogen with similar structure as vitamin E may have sup- emia) was also reported.93 It was found that statins may
pressed oxidative stress due to exercise, thus squelching the impede the activation of ATP and coenzyme Q10 (antioxi-
activation of calpain, a protein with function of diminishing dant), making the muscle cell membrane susceptible to dam-
the infiltration of inflammatory cells such as neutrophil age.44 Similarly, steroids typically used by athletes may also
leukocyte and macrophages.83,84 induce RML and liver damage.94,95 Recently, indication of
RML was reported in a person who performed exercise after
2.4.4. Nutritional problems taking synephrine (similar to phenylpropanolamine or ephed-
Dietary composition of vegetarians with exRML has been rine) contained in supplements used for weight loss.96
discussed previously.85 The amount of ingested protein has Compartment syndrome with RML was also reported in a
been reported to cause variation in the degree of exRML,86 soldier who took ephedrine after completion of physical
suggesting that exRML may be associated with deficiency of training.97 In addition, a woman in her 50s exhibited RML
protein in the diet. Vegetarian athletes, who do not consume together with symptoms of extreme pain, muscle hyposthenia,
proper amount of protein with their meals may potentially and loss of weight and muscle power after taking oriental
develop exRML.87 One young athlete manifested with exRML medicine containing Herba Ephedrae who later died.98
together with high levels of CK, muscle pains, discomfort, RML may be induced by ingestion of drugs such as her-
temporary tachycardia, and retching was found to have been oin, cocaine, amphetamine, and cyclosporine (immunosup-
on vegetarian diet.86 Therefore, healthy diet containing proper pressive agent after organ transplantation).44 Alcohol may
amount of protein is required to prevent exRML. also cause RML by aggravating damage to muscles created
Besides proteins, carbohydrate intake may also play a role by exercise. It was reported that alcohol ingestion after ex-
in exRML. One male marathoner in his 30s who controlled ercise may worsen edema, soreness, and dehydration.99
carbohydrate intake through glycogen loading died from heat Alcohol aggravates muscle damages by innate immuno-
stroke accompanied with exRML and increased levels of CK reactions of the body influenced by differentiated activation
after finishing the race.77 According to Bank,88 among track of inflammatory cells during process of recovery from muscle
and field athletes who exhibited brown urine after glycogen damage.100
loading, were reported to develop acute renal failure. The
manifestation of exRML appeared to originate from acidifi- 2.4.6. Other factors
cation and reduction of normal energy stores in muscles by Various diseases may also affect exRML. A young teenager
increasing lactic acid as results of an increase in glycogen.77 who participated in a weight lifting training had exRML due to
Although the exact mechanism has not been determined, it is an influenza virus.101 In addition, a young basketball player
possible that track and field athletes are more vulnerable to presented with exRML after taking medication to treat influ-
myoglobinuria attributed to glycogen loading.88 Park et al.42 enza.102 Although the exact cause of exRML symptoms needs
suggested that hypokalemia induced by increased insulin further clarification, it is possible that viral infection may play
from excessive intake of carbohydrate may be a possible a role in the cases of exRML.
reason for exRML in a body builder after finishing exercise. Genetic deficiency of metabolic factors may also be
implicated in RML. McArdle’s disease, a deficiency of myo-
2.4.5. Creatine supplements and alcohol phosphorylase related to the metabolism of carbohydrate, may
Creatine supplements have been used by athletes who impede the supply of energy sources required for exercise due
require muscle power in a short time and by general public to the deficiency of enzymes essential for glycolysis and
who may wish to increase the muscle mass.89 Creatine is glycogenolysis.103 Reduction or absence of glycolysis and
endogenous energy substrates that can be taken additionally as glycogenolysis would have a negative influence on the syn-
supplements.90 The intake of 20e25 g/day of creatine for 5e7 thesis of ATP as illustrated in Fig. 1. Fatty acid oxidation
days is recommended. However, over 80% of athletes appear disorders such as the disturbance of b-oxidation and other
to take much larger amount of the supplements than enzyme shave also been linked to RML.104,105 Fatty acid
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6 J. Kim et al.

oxidation is an important energy metabolism system in skel- accompanied with dark urine color are observed 24e48 h after
etal muscles, heart, liver, and kidneys.106 exercise.120
Deficiency of carnitine palmitoyltransferase II may cause
RMLvia synthesis of ATP related to lipid metabolism during
aerobic exercise.107 Deficiency of carnitine palmitoyl-
4. Rehabilitation protocol
transferase II is a common cause of myopathy, resulting in
RML in adults.108
Rehabilitation programs related to RML were introduced
Mutations of lipin 1 (LPIN 1) gene have been suggested as
by Randall et al.68 The initial rehabilitation program should be
a novel factor in recurrent RML,109 and are associated with the
composed of exercise containing gradual resistive exercises to
muscle specific phosphatidic acid phosphatase, a key regulator
activate cell function and prevent energy deficiency. This
in triglyceride biosynthesis.110 This gene, predominantly
would enable the exercise intensity of muscles to be placed
expressed in muscle and adipose tissues,111 affected recurring
below an aerobiosis. In general, the range of motion of joints
RML in children.112 The prognosis of LPIN 1 deficiency has
should improve simultaneously. During the 1st stage of a
been considered as a negative outcome, causing death in one-
rehabilitation program, manual efforts to secure a range of
third of patients with RML.113
motions of joints may require some form of discomfort and
perhaps some pain. Before recovering from complete joint
3. Symptoms and diagnoses mobilization, the 2nd stage of rehabilitation should increase
gradually. The distal portion of the upper or lower part of the
The symptoms of exRML may vary individually. However, body should be manipulated gradually with very low intensity
changes in the color of urine and muscle soreness are com- from 5 to 15 min using a non-weight bearing equipment. If no
mon.114,115 When RML occurs, excessive Mb contained in the feeling of discomfort or pain is present within 24 h after the
urine may exhibit myoglobinuria with dark colors. Extreme exercise, the 3rd stage of the rehabilitation program could be
muscle soreness is accompanied by cramps or muscular introduced. In the 3rd stage of the rehabilitation program,
stiffness, nausea, headache, and fatigue.44,115 isotonic exercises such as stretching of the joints, modified
Blood tests and urinalysis have been adopted to diagnose flexion and extension of joints, or bench press should be
for exRML. CK, Mb, LDH, aspartate aminotransferase (AST), gradually introduced. Modified flexion and extension of joints
troponin, and aldolase in blood are examined via various blood should start from forward tilted position with both hands
tests that also include tests for CK and Mb. CK is the most touching the wall, and then proceed to a table, a footboard, or
sensitive indicator of RML. The normal level of CK is at chairs, and finally to the floor to increase the joint mobility and
22e198 U/L. Depending on the degree of RML, the level of exercise intensity. In the 4th stage of the rehabilitation pro-
CK could increase up to 10,000e200,000 U/L.58 CK level of gram, one set of limited flexion and extension of the joints
3,000,000 U/L was observed in one case report.115 Thus, CK should be performed together with the normal exercise pro-
level in blood has been adopted as an indicator of RML. gram. The limits of flexion and extension of joints is to restore
However, some studies have questioned the diagnosis performance capability before determination of RML without
employing CK.116 It was reported that CK may be sensitive loss of range of motion of joints or pain.68
but not specific for RML.117 The National Lipid Association’s Guidelines of O’Connor et al.121 divide the rehabilitation
Muscle Safety Expert Panel provided the level of CK to di- program in three phases for athletes at low risk for RML. In
agnose RML into three categories: 1) levels less than 10 times the phase 1, CK and urinalysis are monitored during moderate
of the upper limit of normal (ULN) was classified as mild; 2) resting. In phase 2, the guidelines suggest the initiation of
levels of 10e49 times of ULN was classified as moderate; and physical activity. In the phase 3, the guidelines suggest a
3) levels exceeding 50 times of ULN have been classified as gradual comeback to sports activity. They recommend 72 h of
marked.116 rest and ample water intake after the onset of RML in phase 1.
Since Mb can be quickly removed from the serum, it has a Eight hours of sleep has been recommended together with
relatively low reliability as an indicator for RML diag- remaining in a heat-controlled environment in the presence of
nosis.58,118 In urinalysis, the ratio of nitrogen and creatinine RML when accompanied with heat injury. Monitoring of CK
has been determined to be positive when diagnosing for RML. and urinalysis every 72 h has also been recommended. Light
The normal ratio of nitrogen and creatinine is 10:1. This ratio physical activities in phase 2 could be initiated after urinalysis
may decrease below 6:1 depending on the symptoms of results reveal CK levels below five times of the normal level.
RML.44 In addition, electrolyte balance, arterial blood gas In cases where CK or the results of urinalysis are not
examination, muscle biopsy, and/or electrocardiogram are normalized within 2 weeks, medical consultation was rec-
used for the diagnosis of RML.119 Controversy exists that ommended. For phase 2, physical activities considering self-
addresses possible and viable use of biomarkers for detection paced distance should be practiced. The phase 3 could be
of RML. Thus, the determination of RML depends on symp- initiated along with necessary follow-ups when no clinical
toms recognized by exercise participants. Previous study has symptoms a represent during a 1-week follow-up in phase 2.
suggested to seek diagnosis and treatment when pain The rehabilitation program after the onset of RML should be

Please cite this article in press as: Kim J, et al., Exercise-induced rhabdomyolysis mechanisms and prevention: A literature review, Journal of Sport and Health
Science (2015), http://dx.doi.org/10.1016/j.jshs.2015.01.012
 + MODEL

Exercise-induced rhabdomyolysis 7

advanced gradually while carefully monitoring symptoms 5.3. Prudence in participating in exercise when having
(CK, pains, etc.). communicable diseases

Regular exercise may become a risk factor in individuals

5. Prevention guidelines
prone and susceptible to disease. Individuals with mild disease
including communicable diseases should refrain from exer-
5.1. Consideration of exercise program components
cise, or at least limit the scope of the exercise. In cases of viral
diseases including diarrhea or vomiting, exercise and training
It has been suggested that warm-up may be the best
should be modified or abstain from training to prevent possible
approach to improve exercise adherence, as it provides the
development of exRML.130 Symptoms that are similar to those
participant with pre-practice of the actions required for cor-
of influenza or communicable diseases should be considered to
responding exercises or games. Warm-ups could also reduce
avoid further complications.4
the chance or occurrence of musculoskeletal damage.122 It
may also be useful to utilize the same amount of time for
5.4. Environmental factors to be considered in outdoor
warm-up and cool-down as demanded factual exercise or
exercises
game.
Several studies have reported that periodic repetition of
Many previous studies have reported that sufficient intake
eccentric exercises could reduce the level of muscle damage,
of water is effective in preventing heat induced disorders.
inducing positive changes in blood markers such as CK or
Normal hydration could ensure the homeostasis of body
LDH as well as diminished pains of the muscles.123e125 To
temperature.131,132 These relatively simple and common sense
make these changes, several factors should be considered,
measures may prevent heat induced disorders and subse-
including the interval time between each exercise, the number
quently reduce the risk and onset of exRML. Since the degree
of repeated eccentric contractions, length of muscles, and the
of water loss in a high temperature environment is usually
types of exercise. Various mechanisms related to repeated-
higher, coaches and other professional in the field should
bout effect120 have been reported. Changes to muscle fibers
continually observe athletes to prevent exRML. In addition,
and the nervous system would require additional motor units
clothing heat production needs to be considered as well.
for successful eccentric contractions. Thus, muscles should be
American football players often presented with exRML
adapted by considering not only dynamic factors such as
attributed to their heavy and thick uniforms.133 When
length-tension changes, but also reduction in intracellular
participating in exercise in high temperature, wearing clothing
events such as inflammatory reaction generated from damage
and uniforms that would assist and aid in heat dissipation and
or function of excitation-contraction coupling (E-C coupling)
provide a cooling mechanism should be considered.134
to prevent the onset of exRML.126,127
What type of exercise could prevent exRML? The answer
5.5. Consideration of alimentation
to this question is not clear. However, it may be easy to
identify the types of exercises that may promote exRML. CK
Excessive exercise consumes large amounts of body en-
is a crucial indicator for the diagnosis of exRML. High-
ergy. Thus, supplying the body with major nutrients after
intensity, longer-duration, and weight-bearing exercise
completing exercise, including protein, carbohydrates, and fat,
(eccentric contraction and downhill running) have been found
is preferable and prudent practice. When muscles are
to be responsible for the increase in CK concentration,128
damaged, catabolic state may aggravate the damage. These
especially in men who are lacking physical strength.129
changes could be diminished by proper intake of balanced
Thus, the type and intensity of exercise must be considered
nutrients.135 To promote the recovery and regeneration of
prudently before participating in exercises training program.
damaged muscles, ingesting protein together with carbohy-
drate is more effective since carbohydrate improves the rate of
5.2. Education of exercise-induced rhabdomyolysis glycogen synthesis.136,137 Sweating and muscular contraction
may induce excessive loss of electrolytes as results of intense
Generalized guidelines for identification of exRML have exercise or training. Thus, drinking fluids containing electro-
not been established. Individuals participating in exercise lytes during and after exercise is desirable.138 Proper mainte-
requiring greater or more intense eccentric contraction of nance of fluids and nutrients after completing exercise could
muscles should understand the danger and potential exRML to provide damaged muscles with necessary fuel for recovery and
prevent this condition.66 It is also important to educate coaches regeneration and prevent the potential to develop RML.
and others who are involved in training of athletes about the RML is also known to be associated with oxidative stress.
symptoms and signs of exRML. Lack of descriptions Proper intake of exogenous antioxidants could be another way to
regarding the exRML in exercise physiology books and books prevent the onset of RML. Intake of antioxidants, oxidative
addressing physical training are warranted.63 Knowledge of stress caused by ROS may be reduced and prevent the damage or
exRML would enhance coaches and other professional of failure of kidneys.139 Since RML is related to oxidative stress,
athletes in each field to recognize quickly when exRML may the uptake of coenzyme Q10 may improve the activation of
occur.130 endogenous antioxidants such as glutathione, superoxide
Please cite this article in press as: Kim J, et al., Exercise-induced rhabdomyolysis mechanisms and prevention: A literature review, Journal of Sport and Health
Science (2015), http://dx.doi.org/10.1016/j.jshs.2015.01.012
 + MODEL

8 J. Kim et al.

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Please cite this article in press as: Kim J, et al., Exercise-induced rhabdomyolysis mechanisms and prevention: A literature review, Journal of Sport and Health
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