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Overexpression of copperzinc superoxide dismutase A novel cause of murine muscular dystrophy.

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ticaria followed by anhidrosis. Jpn J Clin Dermatol 1984;38:
They reported a lack of difference in the numbers of
619-623
nerve terminals and unmyelinated axons in their patient
0. Ando Y, Fujii S, Sakashita N, et al. Idiopathic acquired idiocompared with 6 control subjects, suggesting the prespathic generalized anhidrosis: clinical manifestations and histoervation of postganglionic sympathetic nerves. Howchemical studies. J Neurol Sci 1995;132:80-83
ever, the patients reported by the latter two g r o ~ p s l ~ , ~ * 1. Low PA, Caskey PE, Tuck RR, et al. Quantitative sudomotor
axon reflex test in normal and neuropathic subjects. Ann Neushowed degeneration of the eccrine glands and inflamrol 1983;14:573-580
matory cell infiltration around the eccrine glands, re2. Muta Y, Ohnishi A, Yamamoto T, Ikeda M. The effect of agspectively.
ing on the active sweat gland density in the dorsum of foot
In our patient, the reduced density of active eccrine
Clin Neurol 1991;31:1 165-1 169
glands, which are morphologically normal looking, sug3. Murakami K, Sohue G, Iwase S, et al. Skin sympathetic nerve
activity in acquired idiopathic generalized anhidrosis. Neurolgests the eccrine glands are preserved but dysfunctional.
ogy 1993;43:1137-1140
Therefore, degeneration of postganglionic sympathetic
4. Muta Y, Ohnishi A, Ohnari K, et al. Idiopathic generalized
cholinergic nerves is the most likely cause of anhidrosis.
acquired anhidrosis. Clin Neurol 1995;35:638-642
Furthermore, the presence of low SSNA burst rate on
microneurography appears to support sympathetic nerve
involvement. However, in our patient, the coexistence of
structural abnormality or functional abnormality of cholinergic receptors could not be ruled out.
Corticosteroid is reported to produce a dramatic effect in some patients with AIGA, although adequate
controls were not examined in these st~dies.*~','~
In
contrast, our patient poorly responded to therapy. It is
likely that the effect of steroid may depend on the nature of pathogenetic process and/or the disease stage.
. AIGA is a rare disease. A careful and systematic exThomas A. Rando, MD, PhD,*
amination of each patient, including quantitative
Rebecca S. Crowley, M D , * Elaine J. Carkon, BS,t
evaluation of the sudomotor function test, microneuCharles J. Epstein, MD,t a n d Prarnit K. Mohapatra, BA'
rographic SSNA recording, light and electron microscopic morphometric examination of eccrine glands
and their nerves and nerve terminals, and cholinergic
Oxidative injury underlies the cellular injury and cell
receptors of glandular cells, may enhance our underdeath in a variety of disease states. In muscular dystrostanding of the pathogenesis of this disease.
phies, evidence from in vivo and in vitro studies suggests
Overexpression of Copped
Zinc Superoxide Disrnutase:
A Novel Cause of Murine
Muscular Dystrophy
We thank Drs T. Mitsushima, T . Nakamura, and Y. Tanaka of the
University of Occupational and Environmental Health, and Dr. H.
Kanazawa of Kanazawa Medical Clinic, for their excellent technical
help and valuable advice in this study.
References
1. Low PA, Fealey RD, Sheps SG, et al. Chronic idiopathic anhidrosis. Ann Neurol 1985;18:344-348
2. Fog M. General acquired anhidrosis. JAMA 1936;107:7204072045
3. Engelhardt HT, Melvin JP Jr. General acquired anhidrosis.
Am J Med Sci 1945;210:323-338
4. Murakami K, Sohue G, Terao S, Mitsuma T . Acquired idiopathic generalized anhidrosis: a distinctive syndrome. J Neurol
1988;235:428-431
5. Terui T , Ohkawa Y, Tagami H. Idiopathic acquired generalized
anhidrosis: electron-microscopic and immunohistochemical
studies and analysis of lectin-binding pattern of the cell membrane. Dermatologica 1989;178:123-125
6. Tsuji T, Yamamoto T . Acquired generalized anhidrosis. Arch
Dermatol 1976;112:1310-1 3 14
7. Nakazato Y, Shimizu K, Tamura N, Hamaguchi K. Idiopathic
pure sudomotor failure. Clin Neurol 1994;34:12-15
8. Kay DM, Maibach HI. Pruritus and acquired anhidrosis: two
unusual cases. Arch Dermatol 1969;100:291-293
9. Aihara M, Hayashi M, Nakajima H. A case of cholinergic ur-
that muscle degeneration may be secondary to an increased susceptibility to oxidative stress. To address the
role of free radical metabolism in the pathogenetic process of muscular dystrophies, we examined the muscle of
transgenic mice that overexpress copperhinc (Cu/Zn) superoxide dismutase. Overexpression of this enzyme can
sensitize cells to oxidative injury, and CuIZn superoxide
dismutase activity was elevated approximately fourfold
above control levels in skeletal muscle of the transgenic
strain. Examination of serum creatine phosphokinase levels in these mice revealed significant elevations after 2
months of age, indicative of active muscle breakdown. By
8 months of age, there was gross atrophy of the quadriceps muscle, and other hindlimb muscles were variably
affected. Histologically, there was evidence of widespread
From the *Department of Veterans Affairs, Palo Alto, and Department of Neurology and Neurological Sciences, Stanford University
School of Medicine, Stanford; and ?Department of Pediatrics, University of California, San Francisco, CA.
Received Dec 18, 1997, and in revised form Mar 6, 1998. Accepted
for publication Mar 19, 1998.
Address correspondence to Dr Rando, Department of Neurology
and Neurological Sciences, Stanford University School of Medicine,
Stanford, CA 94305-5235.
Copyright
0 1998 by the American Neurological Association
381
muscle necrosis and regeneration, fiber splitting, and replacement of muscle with adipose and fibrous connective
tissue, typical of a muscular dystrophy. Associated with
the development of this degeneration was an increase in
the levels of lipid peroxidation in the muscle of Cu/Zn
superoxide dismutase transgenic mice, highlighting the
central role of oxidative injury in this pathogenetic process. These results demonstrate that oxidative damage can
be the primary pathogenetic process underlying a muscular dystrophy.
Rando TA, Crowley RS, Carlson E, Epstein CJ,
Mohapatra PK. Overexpression of copper/
zinc superoxide dismutase: a novel cause
of murine muscular dystrophy.
Ann Neurol 1998;44:381-386
All actively metabolizing cells are in a constant state of
balance between the toxic products they produce and
the cellular mechanisms they possess to limit or repair
the damage from those toxins. Reactive oxygen species,
including oxygen free radicals, are by-products of normal cellular metabolism that can cause injury by oxidation of lipids, proteins, and nucleic acids.' When
free radical production increases or antioxidant defense
mechanisms are impaired, the resulting state of oxidative stress can be associated with irreversible cell injury
and death.
Many diseases and conditions, including atherosclerosis, autoimmune disorders, tissue ischemia, and aging, have been associated with states of oxidative
stress.2 Based on several lines of evidence suggesting
that oxidative injury may be central to the process of
muscle necrosis in muscular d y ~ t r o p h i e s , ~we
- ~ have
explored the susceptibility of muscle to oxidative injury
in dystrophies due to defects in the dystrophin gene.
Dystrophin-deficient muscle appears to be more sensitive to this form of injury,' and muscle fiber necrosis is
preceded by increases in oxidative injury in dystrophindeficient (mdx) mice.'
To explore further the role of oxidative metabolism
in the muscular dystrophies, we have begun to examine
strains of mice that have been genetically altered in
critical pathways of free radical metabolism. O n e of
these is a transgenic strain (designate SOD-tg) that
overexpresses the human copper/zinc superoxide dismutase (Cu/Zn SOD) gene.' Overexpression of C u / Z n
S O D has been shown, under certain circumstances, to
sensitize cells to the effects of oxidative injury.",'
Therefore, we postulated that overexpression of this enzyme might predispose muscle to degenerative changes.
Indeed, we found that overexpression of C u / Z n SOD
results in a progressive muscular dystrophy. This strain
therefore provides an excellent model in which to examine the relationship between oxidative stress and
muscle cell necrosis as it relates to the pathogenetic
processes in the muscular dystrophies.
'
382 Annals of Neurology
Vol 44
No 3
September 1998
Materials and Methods
Animals
SOD-tg mice [designation: CDI-TgN(SOD1)3Cje, CD1TgN(SOD1)IOCje, and C57BL/6-TgN(SOD1)3Cje] and
control CD1 and C57BLi6 mice were maintained at the
Veterinary Medical Unit of the VA Medical Center at Palo
Alto and at the Animal Care Facility at the University of
California, San Francisco. The generation of the transgenic
strains has been described previo~sly.~
All animals were handled in accordance with institutional guidelines. All data presented concerning the transgenic strains were obtained from
mice that were homozygous for the transgene.
Histopathology
For histological studies, muscles were placed in cryomolds
containing embedding medium (O.C.T. compound, Miles
Laboratory, Elkhart, IN) and frozen in isopentane cooled to
- 160°C in liquid nitrogen. Ten-micrometer-thick cross sections were obtained with a Leica cryostat at -20°C. The
sections were collected onto gelatin-coated slides, stained
with hematoxylin and eosin for routine analysis, and examined with a Zeiss Axioskop microscope.
Creatine Phosphokinase Assay
Mice were bled from a tail vein to obtain 100 to 300 pl of
blood. Serum was obtained and creatine phosphokinase
(CPK) measurements were performed by using a commercial
kit (Sigma Chemicals, St Louis, MO) according to manufacturer recommendations. Protein concentrations were determined by using the Bradford reagent (Sigma).
CulZn SOD Assay
Cu/Zn SOD activities were determined according to the
method of Kirby and Fridovich12 with minor modifications.
Whole blood or tissue was homogenized on ice in 50 mM
phosphate buffer containing protease inhibitors (EDTA, phenylmethylsulfonyl fluoride, leupeptin, and aprotinin). The
homogenates were centrifuged at 4,000 g for 20 minutes at
4 ° C and the remainder of the assay is performed at 25°C.
T o 2.4 ml of sample supernatant was added 0.3 ml of 0.1
mM cytochrome c and 0.3 ml of 0.5 mM xanthine. KCN
was added to a final concentration of 10 pM. The reaction
was initiated by the addition of 6 nmol xanthine oxidase,
and absorbance at 550 nm was recorded over time. The activity was determined according to a standard curve generated by using a Cu/Zn SOD standard and is expressed as
units per milligram of protein. Protein concentrations were
determined by using the Bradford reagent (Sigma).
Lipid Peroxidation Assay
Muscle tissue was homogenized and the level of lipid peroxidation was measured by using the thiobarbituric acid assay kit
according to manufacturer recommendations (CalbiochemNovabiochem, San Diego, CA). This assay determines levels
of malondialdehyde and 4-hydroxy-2(E)-nonenal,which ptovide an index of lipid per~xidation.'~
Results are presented as
equivalent nanomoles of malondialdehyde per milligram of
protein. Protein concentrations were determined by using the
Bradford reagent (Sigma).
A
SOD'"
C
Control
1
f'OO
x
*
T
T
0 control
SOD-tg
Age Range (mos)
Statistical Analysis
For the biochemical assays, statistical comparisons were done
by using analysis of variance, and differences were considered
to be statistically significant at p < 0.05.
Fig I . Muscular dystrophy in SOD-tg
mice. (A) Gross and microscopic appearance. Quadriceps muscles of
8-month-old SOD-tg and age-matched
CD-I control mice were examined
grossly and microscopically. (Top) Profound atrophy was apparent in the
SOD-tg quadriceps muscle (arrows)
compared with the normal bulk in the
control. (Bottom) Microscopic sections
of the muscles stained with hematoxylin
arid eosin are shown. The muscle of
the SOD-tg mouse displayed evidence
of a severe muscular dystrophy. There
was replacement of muscle tissue with
adipose and fibrous connective tissue,
most of the remaining fibers bad central nuclei, and there were fibers undergoing active degeneration. The
control muscle was normal.
(Magnification, X 200 before 10%
reduction.) (B) Temporal progression:
(a) At 3 weeks of age, no signs of muscle degeneration were present. (6) At
2.5 months of age, the first signs of the
disease were rare necrotic fibers. (c) At
3.5 months of age, occasional necrotic
fibers and scattered centrally nucleated
fibers were evident, as well as some
increase in interstitial connective tissue.
(Magnification, X 200 before 10%
reduction.) (C) Serum creatine phosphokinase (CPK) leueh. Serum was
obtained fiom control and SOD-tg
mice at different ages and assayedfor
CPK activity (see Materials and Methods). Samples were grouped according
to the age ranges indicated. Each value
represents the mean of at least 4 separate animals, and error bars represent f SD. The CPK values for the
SOD-tg mice were signij5cantly greater
than age-matched controls in the 2- to
5-month and 5- to 9-month age
ranges. *p < 0.05.
Results
The SOD-tg mice developed increasing difficulty with
their gait with age. No abnormalities were obvious in
young mice, but after about 8 months of age the mice
Brief Communication: Rando et al: Overexpression of Cu/Zn SOD
383
appeared to waddle compared with nontransgenic mice
of the same age. In 8-month-old mice, dissection of the
hindlimb muscles revealed moderate to severe atrophy
of individual muscles (Fig lA, top panels). O n histological examination, the muscles demonstrated degenerative changes with all of the hallmarks of a muscular
dystrophy (see Fig lA, bottom panels). In the quadriceps muscle, the muscle tissue was substantially replaced by adipose and connective tissue, there was a
wide variation in muscle fiber size with fiber splitting,
and there was evidence of ongoing fiber necrosis and
regeneration. Most of the fibers at this age had central
nuclei and evidence of previous necrosis and regeneration. Among the skeletal muscles examined, the pathology was most severe in the quadriceps and gastrocnemius, moderate in the soleus and tibialis anterior, mild
in the extensor digitorum longus, and negligible in the
diaphragm.
We examined muscles from mice of different ages to
determine the progression of the disease (see Fig IB).
Up to 2 months of age, we saw no evidence of fiber
necrosis. Between 2 and 3 months of age, necrotic fibers were detectable in hindlimb muscles. By 4 months
of age, there were many fibers with central nuclei and
there was active necrosis of individual fibers and groups
of fibers. This histological progression paralleled a rise
in serum CPK as would be expected for a degenerative
disorder of muscle. Measurement of serum CPK values
revealed that while CPK levels were normal in SOD-tg
mice during the first weeks of life, a significant eleva-
tion was present in SOD-tg mice over 2 months of age
compared with controls (see Fig 1C).
T o determine whether the onset of changes in muscle pathology was associated with changes in transgene
expression, we measured Cu/Zn SOD activity as a
function of age. Cu/Zn SOD activities were determined in peripheral blood cells and were found to be
elevated approximately fivefold above control levels, as
had been reported for SOD-tg strains.’ The level of
Cu/Zn SOD activity, which represents both transgenic
and endogenous Cu/Zn SOD, did not change significantly with age in the transgenic mice (Fig 2). We also
measured Cu/Zn SOD activities in limb muscle to determine if there were tissue-specific alterations in expression that changed with age. Again, the activities in
SOD-tg muscle were elevated compared with controls
(four- to five-fold), and total muscle Cu/Zn SOD activity did not change significantly across this age range
in either transgenic or control mice. In addition, there
were no significant differences in the Cu/Zn SOD activities among the different hindlimb muscles tested,
including muscles that were differentially affected (gastrocnemius [n = 51, 22.0 -t 2.6 U/mg of protein; tibialis anterior [n = 51, 21.0 -t 2.0 U/mg of protein).
To rule out the possibility that our findings were
due to the insertion site (chromosome 3 ) of the Cu/Zn
SOD transgene in the strain described above, we examined mice from a strain [designation: CD1TgN(SOD1)lOCjel in which the transgene was inserted on chromosome 10 instead of chromosome 3.
Fig 2. Copperhinc-superoxide dismutase (Cu/Zn SOD) activity in peripheral blood cells and muscle. CulZn SOD activity was measured in peripheral blood cells (A) and skeletal muscle (B) in SOD-tg and control mice. No significant change is activity was seen
over the age ranges examined in the transgenic mice, suggesting that the onset and progression of muscle degeneration were not due
to age-related changes in transgene expression. For nontransgenic controls, there also was no signijkant change in CulZn SOD activity over this age range. Data are mean t- SD values.
PERIPHERAL BLOOD CELLS
SKELETAL MUSCLE
25
20
T
T
0 control
SOD-tg
0
0-2
2-5
0
5-9
0-2
384
B
Annals of Neurology
Vol 44
No 3
5-9
Age Range (mos)
Age Range (mos)
A
2-5
September 1998
T o rule out the possibility that the pathological
changes were unique to the genetic background of the
mice (CDl), we examined mice in the 13th backcross
generation of the transgene on a C57BL/GJ background [designation: C57BL/G-TgN(SOD 1)3Cje]. For
both of these transgenic strains, serum CPK values
were elevated two- to threefold above control values
after 2 months of age. At 3 months of age, we observed
fibers undergoing active necrosis and an increase in the
number of fibers with centrally placed nuclei (evidence
of regeneration) in muscle from both strains. At this
early stage, the phenotype in the C57 mice appeared ro
be less severe. Phenotypic variability based on strain
background is well recognized in transgenic studies,'*
and colonies of these mice are being backcrossed onto
different strain backgrounds and the colonies expanded, to explore these variations in greater detail.
Nevertheless, our finding of muscle degeneration regardless of transgene insertion site and strain background is further evidence that overexpression of SOD
is the cause of the muscle pathology.
Finally, to confirm that overexpression of Cu/Zn
SOD caused oxidative injury as predicted, we examined muscle of SOD-tg and control mice for evidence
of lipid peroxidation. Lipid peroxidation is commonly
used as a measure of oxidative damage to a cell, and
extensive lipid peroxidation leads to membrane disruption and necrotic cell death.' We used the thiobarbituric acid assay to determine the extent of oxidative
injury in SOD-tg and control muscle over different age
ranges. The extent of lipid peroxidation was greater in
SOD-tg mice compared with controls, and increased in
parallel with the histological progression (Fig 3). These
data support the causal relationship between increases
in CulZn SOD activity and muscle degeneration.
Discussion
The results indicate that overexpression of Cu/Zn
SOD in muscle is a direct cause of muscle degeneration with all the pathological characteristics of a muscular dystrophy. Although increases in Cu/Zn SOD activity have been shown to protect cells against acute
oxidative damage in many instances,' 5,16 several reports have demonstrated that overexpression of Cu/Zn
SOD can sensitize cells to the toxic effects of both
The mechanism
acute and chronic oxidative stress.
of this sensitization has been postulated to occur from
an imbalance between Cu/Zn SOD, which converts
superoxide to hydrogen peroxide, and the enzymes that
detoxify hydrogen peroxide, namely, glutathione peroxidase and catalase."~" In the case of such an imbalance, increased hydrogen peroxide levels could lead to
increased hydroxyl radical formation and cellular damage. Indeed, in a recent report, Peled-Kamar and associates" reported elevated levels of hydroxyl radical in
SOD-tg muscle compared with controls. This finding
'
n
.-E
*
121
*
T
Q)
.c)
0
h
a
0 control
Lm
W SOD-tg
0 - 2
2 - 5
5 - 9
Age Range (mos)
Fig 3. Oxidative injury in SOD-tg mouse muscle. The extent
of oxidative injury was assessed by memuring levels of lipid
peroxidation in hindlimb muscle by using the thiobarbituric
acid assay (see Materials and Methods). Lipid peroxidation
was determined as levels of malondialdehyde (MDA) equivalents and normalized to protein levels in tbe samples. Lipid
peroxidation was greater in SOD-$ mice compared with controls in the 2- to 5-month and 5- to 9-month age ranges.
Each bar represents the average of f . u r separate determinations. Data are mean t- SD values. *p < 0.05.
is direct evidence of the mechanism of toxicity in
SOD-tg mice leading to cellular injury and muscle fiber necrosis.
In addition, these results extend our hypothesis of
the role of oxidative injury in muscular dystrophies.','
In mdx mice, the pathogenetic mechanisms leading to
cell death have remained elusive, in part because the
role of dystrophin in normal cellular metabolism is unknown. l 9 Our recent results suggest that dystrophin
deficiency is associated with an increased susceptibility
to oxidative injury' and that there is evidence of oxidative injury in mdx muscle before the onset of muscle
necrosis.' The SOD-tg mouse provides an interesting
model for the study of this mechanism of cellular toxicity. Similarities and differences between the muscular
dystrophy in SOD-tg mice and that in the mdx strain
may help to shed light on the role of dystrophin
in protecting muscle from necrotic degeneration and
the biochemical pathways of oxidative toxicity in
dystrophin-deficient muscle.
Finally, the SOD-tg strains provide a model in
which to study oxidative metabolism and antioxidant
defense mechanisms in muscle. T o date, no muscular
dystrophy in humans has been linked directly to abnormalities of superoxide dismutase or other antioxidant enzyme activity. However, this has not been tested directly
in dystrophies of unknown genetic basis. Furthermore,
variations in antioxidant defense mechanisms may explain, in part, variations in disease severity in dystrophies
Brief Communication: Rando et al: Overexpression of Cu/Zn SOD
385
in which free radical injury may play a central pathogenetic role. One of the enigmas of the muscular dystrophies, in general, is the selective involvement and specific sparing of specific muscle groups." Such appears to
be the case with the SOD-tg strains as well, although the
level of transgene expression was similar among muscles
that were differentially affected. By understanding how a
muscle or group of muscles can resist the degeneration
that is occurring in adjacent muscles of similar size, similar function, similar embryological origin, and similar
biochemical makeup, novel therapeutic approaches to
the treatment of this heterogeneous group of genetic disorders may be suggested.
4. Gerlai R. Gene-targeting studies of mammalian behavior: is it
5.
6.
17.
18.
This study was supported by grant AGO8938 from the National
Institute on Aging to Dr Epstein and by grants from the Department of Veterans Affairs, the Muscular Dystrophy Association, and
the American Academy of Neurology Education and Research
Foundation to Dr Rando.
19.
20.
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mice. Neurology 1997;48(Suppl 2):A442 (Abstract)
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with increased Cu/Zn-superoxide dismutase activity: animal
model of dosage effects in Down syndrome. Proc Natl Acad Sci
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Vol 44
No 3
September 1998
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