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Creatine supplementation results in elevated phosphocreatineadenosine triphosphate (ATP) ratios in the calf muscle of athletes but not in patients with myopathies.

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LETTERS
Creatine Supplementation Results in Elevated
Phosphocreatine/Adenosine Triphosphate (ATP)
Ratios in the Calf Muscle of Athletes but Not
in Patients with Myopathies
J. Zange, PhD,1 C. Kornblum, MD,2 K. Müller, MD,1
S. Kurtscheid, MSc,3 H. Heck, MD,3 R. Schröder, MD,2
T. Grehl, MD, PhD4 and M. Vorgerd, MD4
In a recent article, Tarnopolsky and Beal1 described the potential benefit of oral creatine supplementation for symptomatic therapy for various muscle diseases. Creatine uptake by
the muscle fibers results in an elevation of intracellular phosphocreatine (PCr) levels because of the equilibrium reaction
of creatine kinase. The uptake is mediated by a creatine
membrane transporter. However, reduced concentrations of
this transporter protein were found2 in various neuromuscular disorders. The aim of this letter is to compare the effects
of oral creatine supplementation on PCr levels in the calf
muscles of sports students performing regular muscle training, of sedentary healthy subjects, and of patients with glycogen storage disease V (McArdle’s disease), chronic progressive external ophthalmoplegia, and X-chromosomal Beckertype muscular dystrophy. All supplementation studies
followed a double-blind, placebo-controlled crossover design.
The creatine dose and the duration of each treatment phase
are summarized in the table. Noninvasive 31P magnetic resonance spectroscopy was performed with a 4.7T magnetic
resonance instrument (81MHz for 31P) and a 5cm surface
coil. 31P magnetic resonance spectra of the right calf were
recorded at rest and analyzed for the integrals of the PCr and
the ␤-ATP signals. Integral values were corrected for partial
spin saturation effects. ATP levels were assumed to be constant throughout the period. In conclusion, PCr/ATP ratios
predominantly reflected alterations in PCr levels.
The PCr/ATP ratio of nontreated sedentary control subjects (n ⫽ 38) was 3.7 ⫾ 0.5. This ratio was significantly
higher than the placebo values of the PCr/ATP ratio in
sports students and in patients with chronic progressive external ophthalmoplegia and X-chromsomal Becker-type muscular dystrophy. Only the sports students profited from creatine supplementation by a significantly increased PCr/ATP
ratio. In the sedentary healthy subjects (n ⫽ 5) and in all
patient groups, muscle PCr/ATP ratios were not significantly
altered with creatine treatment. PCr concentrations in pa-
tient muscle were not augmented, although creatine serum
concentrations were increased by the supplementation (data
not shown) and patients with X-chromsomal Becker-type
muscular dystrophy and chronic progressive external ophthalmoplegia exhibited a lower PCr/ATP ratio than healthy
controls.
In contrast to sports students, sedentary healthy subjects
and patients did not perform regular physical training. In
conclusion, physical exercise might be an essential prerequisite to stimulate the uptake of creatine in skeletal muscle fibers.
1
German Aerospace Center (DLR), Cologne, Germany,
Department of Neurology, University of Bonn, Germany,
3
Institute of Sportsmedicine, Ruhr-University Bochum,
Germany, and 4Department of Neurology, Ruhr-University
Bochum, Germany
2
References
1. Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol 2001;49:561–574.
2. Tarnopolsky MA, Parshad A, Walzel B, et al. Creatine transporter and mitochondrial creatine kinase protein content in myopathies. Muscle Nerve 2001;24:682– 688.
DOI 10.1002/ana.10197
Reply
Mark A. Tarnopolsky, MD, PhD
Creatine has been shown to attenuate calcium accumulation
and improve myocyte survival in cultured dystrophic skeletal
muscle.1 A recent study found an attenuation of muscle necrosis in type 2 fibers and improved mitochondrial respiration capacity in creatine-supplemented dystrophic mice.2
These studies provided theoretical support for the observed
improvement in muscle function demonstrated in a randomized, double-blind crossover trial of creatine monohydrate
supplementation in patients with muscular dystrophy.3 In a
recent longer term study, our group did not find improved
strength or muscle function in 96 patients with muscular
dystrophy who were administered creatine monohydrate for
a period of 4 months. We also did not find increases in mus-
Table. Effects of Oral Cr Supplementation on the PCr/ATP Ratio Measured by
n
Age (yr)
Dose (mg/day⫺1 kg)
Duration (wk)
PCr/ATP placebo
PCr/ATP creatine
p
a
31
P-MRS in Calf Musclesa
Sports Students
Sedentary Subjects
McArdle’s Patients
CPEO Patients
18
25 ⫾ 3
75 ⫾ 10
1
3.3 ⫾ 0.3
4.2 ⫾ 0.7
⬍0.001
5
35 ⫾ 7
150, 60
1, 4
3.8 ⫾ 0.4
3.5 ⫾ 0.3
0.41
14
35 ⫾ 11
150
5
3.8 ⫾ 0.5
4.0 ⫾ 0.6
0.09
15
49 ⫾ 9
150
6
3.2 ⫾ 0.2
3.4 ⫾ 0.3
0.31
BMD Patients
4
⫾4
150
5
2.9 ⫾ 0.4
2.8 ⫾ 0.3
0.79
29
Includes sports students, sedentary healthy subjects, and patients with glycogen storage disease V (McArdle’s disease), CPEO, and BMD.
PCr ⫽ phosphocreatine; ATP ⫽ adenosine triphosphate; CPEO ⫽ chronic progressive external ophthalmoplegia; BMD ⫽ X-chromosomal
Becker-type muscular dystrophy.
126
© 2002 Wiley-Liss, Inc.
cle phosphocreatine in a subgroup of 25 patients, as determined by phosphorus-31 magnetic resonance spectroscopy
(Tarnopolsky, Mark, MD, PhD, Biggar, Doug, MD, Naylor,
Heather, MSc, Thompson, Terry, PhD, Mahoney, Doug,
MSc, Vajsar, Jiri, MD, and Doherty, Timothy, MD, PhD,
unpublished data, 2002). Our findings were consistent with
those reported by Zange and colleagues, in which creatine
supplementation was shown to increase phosphocreatine/
adenosine triphosphate ratios in young healthy sport students
but not in patients with McArdle’s disease chronic progressive external opthalmoplegia or Becker’s muscular dystrophy.
Collectively, our data and those from Zange and colleagues
are consistent with the fact that creatine supplementation
does not increase phosphocreatine content in skeletal muscle
in patients with a variety of neuromuscular disorders at doses
that have been demonstrated to do so in young healthy sport
students.
The main hypothesis the authors used to explain these
findings was that physical activity may be an essential prerequisite for an increase in creatine uptake. Although acute
muscle contraction does increase creatine uptake,4 in one of
the seminal papers looking at creatine monohydrate supplementation, the healthy active students did not perform any
physical activity during the study and still showed an increase in total creatine (but not phosphocreatine).5 These
findings, and the fact that a recent study found that muscle
total creatine increased with creatine supplementation in a
leg that was immobilized for 3 weeks in a cast,6 suggest that
factors other than immobilization may account for the lack
of an increase in phosphocreatine in patients with neuromuscular disease. Such factors as a reduction in the creatine
transporter in muscular dystrophy may play a role in an attenuated ability to retain creatine in skeletal muscle.7
Another important consideration is that creatine monohydrate supplementation usually results in a greater and more
consistently documented increase in muscle total creatine
than phosphocreatine,5 yet phosphorus-31 magnetic resonance spectroscopy only measures phosphocreatine. This is
important, as some of the potential benefits of creatine supplementation may be attributable to an increase in total cellular creatine stores, and not to phosphocreatine per se.8 Furthermore, no study has examined whether creatine
monohydrate supplementation can increase muscle total creatine stores in any neuromuscular disorder. There are still a
number of outstanding issues regarding the transport, retention, dose, and role of creatine in patients with neuromuscular disorders that must be addressed in the near future.
Given the potential for creatine monohydrate supplementation as adjunctive therapy in neuromuscular disorders,1,2,8
and the fact that several randomized trials are under way,
further evaluation of these concepts is warranted to evaluate
the outcomes appropriately.
Departments of Neurology, Physical Medicine and
Rehabilitation, McMaster University, Hamilton,
Ontario, Canada
References
1. Pulido SM, Passaquin AC, Leijendekker WJ, et al. Creatine supplementation improves intracellular Ca2⫹ handling and survival
in mdx skeletal muscle cells. FEBS Lett 1998;439:357–362.
2. Passaquin AC, Renard M, Kay L, et al. Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice. Neuromuscul Disord 2002;12:
174 –182.
3. Walter MC, Lochmuller H, Reilich P, et al. Creatine monohydrate in muscular dystrophies: a double-blind, placebo-controlled
clinical study. Neurology 2000;54:1848 –1850.
4. Robinson TM, Sewell DA, Hultman E, Greenhaff PL. Role of
submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle. J Appl Physiol 1999;87:
598 – 604.
5. Hultman E, Soderlund K, Timmons JA, et al. Muscle creatine
loading in men. J Appl Physiol 1996;81:232–237.
6. Hespel P, Eijnde BO, Van Leemputte M, et al. Oral creatine
supplementation facilitates the rehabilitation of disuse atrophy
and alters the expression of muscle myogenic factors in humans.
J Physiol 2001;536:625– 633.
7. Tarnopolsky MA, Parshad A, Walzel B, et al. Creatine transporter and mitochondrial creatine kinase protein content in myopathies. Muscle Nerve 2001;24:682– 688.
8. Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol 2001;49:561–574.
DOI: 10.1002/ana.10198
Rabbit Model of Guillain-Barré Syndrome
Irving Nachamkin, PhD
Yuki and colleagues1 recently described a rabbit model of
axonal Guillain-Barré syndrome (GBS) after immunization
with bovine brain gangliosides. Although the model is extremely interesting and has potential for studying the pathogenesis of GBS, the method used to immunize rabbits raises
some concerns about the level of pain and distress inflicted
on the rabbits. Briefly, several milligrams of the ganglioside
mixture were mixed with keyhole limpet hemocyanin and
administered with complete Freund’s adjuvant (CFA) via the
subcutaneous and intraperitoneal route at 3-week intervals
until limb weakness developed or 6 months had passed after
the first inoculation.
CFA may cause several local and systemic pathological responses if not used properly, and the repeated use of CFA in
these experiments is particularly concerning. The normal
routes for the injection of CFA are intramuscular, subcutaneous, and intradermal.2 Rabbits given subcutaneous booster
injections with CFA 3 to 6 weeks after inoculation were
prone to develop acute dyspnea, increased respiratory rates,
and serous to serohemorrhagic nasal discharges in studies reviewed by Broderson.2 Congestion of the tracheal mucosa,
laryngeal edema, and severe edema of the lungs were observed on autopsy in rabbits given multiple CFA injections.2
Therefore, if CFA is used for immunization, it should be
used only in small quantities for initial immunization, and
repeated injections of CFA should not be performed, as was
performed in the rabbit GBS model. The authors did not
discuss the rationale for using multiple injections of CFA.
Did they try alternative methods for immunization before
proceeding with the current experiments? One might hypothesize that repeated injections of CFA led to a severe systemic inflammatory response that contributed to the success
of the model; however, the authors did not report a pathological analysis other than for the nervous system.
Annals of Neurology
Vol 52
No 1
July 2002
127
It is unlikely that the protocol used by Yuki and colleagues would ever be approved for an animal research protocol at institutions in the United States, and alternative approaches for reproducing this model of GBS should be
developed.
Department of Pathology and Laboratory Medicine, University
of Pennsylvania School of Medicine, Philadelphia, PA
References
1. Yuki N, Yamada M, Koga M, et al. Animal model of axonal
Guillain-Barré syndrome induced by sensitization with GM1
ganglioside. Ann Neurol 2001;49:712–720.
2. Broderson JR. A retrospective review of lesions associated with
the use of Freund’s adjuvant. Lab Anim Sci 1989;39:400 – 405.
DOI 10.1002/ana.10223
Reply
Nobuhiro Yuki, MD, PhD, Izumi Mori, MD, and
Keiichiro Susuki, MD, PhD
When we read the letter by Dr Nachamkin, we noted that
repeated injections of complete Freund’s adjuvant (CFA)
should not be performed. We agree with him that alternative
approaches are required for reproducing our disease model.1
Because we believe this disease model helps to clarify the
molecular pathogenesis of axonal Guillain-Barré syndrome
(GBS) and to develop new treatments for it, we have decided
to investigate whether our disease model can be reproduced
with incomplete Freund’s adjuvant (IFA) for the second immunization or thereafter. Within several months, we will be
able to show preliminary results for other investigators and
their rabbits. Here we describe some useful information to be
followed up by other laboratories.
In 1989, we found two patients with axonal GBS who
had anti-GM1 immunoglobulin G antibody during the acute
phase of the syndrome, and we reported on them elsewhere.2
In 1990, we intradermally administered 2mg of GM1 and
methylated bovine serum albumin (BSA) with CFA to five
rabbits several times according to the procedure of Nagai and
colleagues,3 but their disease model could not be reproduced.
They used male Japanese white rabbits, whereas we chose
female New Zealand white rabbits. Thomas and colleagues4
immunized New Zealand white rabbits with 1mg of GM1
and methylated BSA. For the first immunization, CFA was
used; thereafter, IFA was used. Their rabbits did not develop
limb weakness, although pathological studies showed mild
axonal degeneration and immunoglobulin deposit at the
nodes of Ranvier. In this journal, in 1996, Kusunoki and
colleagues5 reported experimental sensory neuropathy induced by sensitization with 500␮g of GD1b and keyhole
limpet hemocyanin (KLH) with CFA. They used female Japanese white rabbits, into which a 1ml sample of the emulsion
was injected intradermally at multiple sites on the hind feet.
Booster injections of the same emulsion were given intradermally 3 weeks later at multiple sites on the back.
On the basis of the successful studies of Nagai and colleagues3 and Kusunoki and colleagues,5 we chose male Japanese
white rabbits, into which 2.5mg of Cronassial (a bovine brain
ganglioside mixture containing 500␮g of GM1; Fidia, Padova,
128
Annals of Neurology
Vol 52
No 1
July 2002
Italy) or 500␮g of Sygen (isolated GM1 from bovine brain;
Fidia) and KLH (Sigma, St. Louis, MO) with CFA (Sigma) was
injected subcutaneously to the back, not to the footpads, and
intraperitoneally at 3-week intervals. Because cases of GBS after
ganglioside treatment were reported in Italy, Cronassial and Sygen, which had been available on the Italian market, were used.
All 13 rabbits inoculated with Cronassial developed acute axonal
neuropathy, whereas 9 of 11 rabbits sensitized with Sygen did.
As described in the article cited by Dr Nachamkin,6 the inflammatory reaction with the subcutaneous route was severe but localized: the intraperitoneal inoculation produced the formulation of multiple focal granulomas, diffuse fibrinous peritonitis,
and serofibrinous ascites.
According to the reported procedure,1 male Japanese white
rabbits were immunized by 0.5, 1, or 2.5mg portions of Cronassial subcutaneously to the back at a few sites; 0 of 3, 3 of 6,
and 6 of 6, respectively, developed severe flaccid weakness.7
The appropriate amount of Cronassial was thought to be
2.5mg, and the intraperitoneal inoculation was not required.
Of 8 rabbits inoculated with 500␮g of GM1 (Sigma), 3
showed severe weakness, indicating that not only Sygen but
also purified GM1 could induce acute axonal neuropathy.
Last year, we received an e-mail message from Dr
Nachamkin’s institute about address of Japan SLC Inc.
(Hamamatsu, Japan), from which we obtained Japanese white
rabbits (JW/CSK). Other investigators asked us whether the
disease model could be reproduced in New Zealand white rabbits. Therefore, we investigated how the immunization procedure could be reproduced more easily in other laboratories (I.
Mori, Y. Nishimoto, and N. Yuki, unpublished data, 2001).
The ganglioside mixture was prepared from bovine brain in
our laboratory. Rabbits weighing 2.0 to 2.5kg were obtained
from Oriental Bioservice Kanto (Tsukuba, Ibaraki, Japan). On
sensitization with the ganglioside mixture and KLH with CFA
subcutaneously to the back at 3-week intervals, both male
(n ⫽ 3) and female (n ⫽ 3) Japanese white rabbits (Kbs:JW)
showed limb weakness. The three male Japanese white rabbits
developed flaccid paralysis 35, 57, and 60 days after the first
inoculation, whereas 2 of 3 male New Zealand white rabbits
(Kbs:NZW) developed flaccid paralysis at 61 and 97 days after
the first inoculation of the ganglioside mixture and KLH with
CFA. Of 3 male Japanese white rabbits immunized by the
ganglioside mixture and methylated BSA (Sigma), 1 developed
limb weakness 97 days after the first inoculation. Serological
and pathological studies should be performed. The preliminary results indicate that flaccid paralysis could be induced in
New Zealand white rabbits, but we believe it is better to
choose Japanese white rabbits. As a carrier protein, KLH, not
methylated BSA, should be chosen.
Department of Neurology, Dokkyo University School of
Medicine, Tochigi, Japan
References
1. Yuki N, Yamada M, Koga M, et al. Animal model of axonal
Guillain-Barré syndrome induced by sensitization with GM1
ganglioside. Ann Neurol 2001;49:712–720.
2. Yuki N, Yoshino H, Sato S, Miyatake T. Acute axonal polyneuropathy associated with anti-GM1 antibodies following Campylobacter enteritis. Neurology 1990;40:1900 –1902.
3. Nagai Y, Momoi T, Saito M, et al. Ganglioside syndrome, a new
autoimmune neurologic disorder, experimentally induced with
brain gangliosides. Neurosci Lett 1976;2:107–111.
4. Thomas FP, Trojaborg W, Nagy C, et al. Experimental autoimmune neuropathy with anti-GM1 antibodies and immunoglobulin deposits at the nodes of Ranvier. Acta Neuropathol (Berl)
1991;82:378 –383.
5. Kusunoki S, Shimizu J, Chiba A, et al. Experimental sensory
neuropathy induced by sensitization with ganglioside GD1b.
Ann Neurol 1996;39:424 – 431.
6. Broderson JR. A retrospective review of lesions associated with
the use of Freund’s adjuvant. Lab Anim Sci 1989;39:400 – 431.
7. Susuki K, Yuki N, Baba M, Ueda S, Hirata K. Animal model of
axonal Guillain-Barré syndrome: electrophysiological and immunohistochemical study. J Peripher Nerv Syst 2001;6:180 –181
(Abstract).
Editor’s note: In considering adjuvant use, see Jackson LR,
Fox JG. Institutional policies and guidelines on adjuvants
and antibody production. ILAR J 1995;37:141–152.
DOI 10.1002/ana.10228
Mistaken Treatment of Anterior Ischemic Optic
Neuropathy with Interferon ␤-1a
Jonathan C. Horton, MD, PhD
For patients with optic neuritis, interferon ␤-1a treatment to
prevent future demyelinating events represents a signal advance.1 After a first attack of optic neuritis, current practice
is to obtain magnetic resonance imaging (MRI) scan in
search of silent brain lesions. If more than one demyelinating
plaque is present, interferon ␤-1a treatment often is recommended. In the past 6 months, I have examined three patients with nonarteritic anterior ischemic optic neuropathy
(AION) and incidental vascular MRI white matter lesions
who were erroneously prescribed weekly interferon ␤-1a injections for the prevention of multiple sclerosis. A typical
case follows.
A 52-year-old woman developed acute, painless optic disc
edema in her right eye. Visual acuity was reduced to 20/100.
Two years later, a similar attack occurred in the left eye, with
loss of visual acuity to 20/400 (Fig 1). An MRI scan showed
more than a dozen scattered white matter lesions on T2weighted spin-echo sequences. The patient received a diagnosis of a second attack of optic neuritis and was treated
with interferon ␤-1a for multiple sclerosis.
Optic neuritis and AION sometimes are confused, because they have overlapping clinical profiles.2 When optic
disc edema occurs in optic neuritis, the fundus appearance
can closely resemble AION.3 In both conditions, a second
attack in the other eye is common. Finally, in both conditions, MRI often shows multiple, small, T2 white matter lesions. The demyelinating plaques of multiple sclerosis can be
difficult to distinguish from the lesions of subcortical arteriosclerotic encephalopathy, which are associated with AION
and vascular disease.4
Cogan was aware that AION often is misdiagnosed but
Fig 1. (top) Pallor of the right optic disc from old anterior
ischemic optic neuropathy and edema of the left optic disc
from an acute attack. (bottom) Axial T2-weighted magnetic
resonance images showing white matter lesions that were confused with demyelinating plaques.
concluded that “the differentiation from true optic neuritis is
not of great importance since treatment of either is simply
palliative.”5 With the advent of interferon ␤-1a therapy, it
has become vital to differentiate accurately between AION
and optic neuritis. Features suggesting AION are lack of
pain, poor visual recovery, older age, optic disc hemorrhage,
and sectorial optic disc edema. AION accompanied by cerebral white matter lesions can masquerade as multiple sclerosis.
Beckman Vision Center, University of California,
San Francisco, San Francisco, CA
References
1. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon
beta-1a therapy initiated during a first demyelinating event in
multiple sclerosis. N Engl J Med 2000;343:898-904.
2. Rizzo JF, Lessell S. Optic neuritis and ischemic optic neuropathy. Arch Ophthalmol 1991;109:1668-1672.
3. Warner JEA, Lessell S, Rizzo JF, Newman NJ. Does optic disc
appearance distinguish ischemic optic neuropathy from optic
neuritis? Arch Ophthalmol 1997;115:1408-1410.
4. Uhlenbrock D, Sehlen S. The value of T1-weighted images in
the differentiation between MS, white matter lesions, and subcortical arteriosclerotic encephalopathy (SAE). Neuroradiology
1989;31:203-212.
5. Cogan DG. Neurology of the visual system. 4th ed. Springfield
IL: Thomas, 1980:178.
DOI: 10.1002/ana.10269
Annals of Neurology
Vol 52
No 1
July 2002
129
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