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P-31 Magnetic Resonance Spectroscopy in Polymyositis and Dermatomyositis.

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199
P-31 MAGNETIC RESONANCE SPECTROSCOPY IN
POLYMYOSITIS AND DERMATOMYOSITIS
Altered Energy Utilization During Exercise
ERIC D. NEWMAN and ROBERT J. KURLAND
Objective. To explore alterations in energy utilization as a potential etiology for weakness in polymyositis and dermatomyositis (PM/DM).
Methods. P-31 magnetic resonance spectroscopy
studies were performed in patients with acute and
treated PM/DM and in normal controls, at rest and with
exercise.
Results. Patients with acute and treated PM/DM
showed increased ratios of inorganic phosphate to phosphocreatine (PCr) during exercise, with loss of ATP
disproportional to loss of PCr.
Conclusion. This study demonstrates changes in
energy utilization in PM/DM, thus supporting the notion
of a metabolic etiology for the weakness associated with
these diseases.
The etiology of the proximal weakness found in
patients with polymyositis and dermatomyositis (PM/
DM) remains obscure. In previous studies, it has been
difficult to correlate weakness in these diseases with
other measures of disease activity, such as creatine
phosphokinase (CPK) levels or inflammation seen on
muscle biopsy (1,2). Although muscle damage might
be underestimated due to sampling error on biopsies, it
From the Department of Rheumatology and the Department
of Radiology, Geisinger Medical Center, Danville, Pennsylvania.
Supported by a grant from the Geisinger Clinic Research
Fund.
Eric D. Newman, MD, FACP: Department of Rheumatology; Robert J. Kurland, PhD: Department of Radiology.
Address reprint requests to Eric D. Newman, MD, FACP,
Department of Rheumatology, Geisinger Medical Center, Danville,
PA 17822.
Submitted for publication June 7, 1991; accepted in revised
form October 1, 1991.
Arthritis and Rheumatism, Vol. 35, No. 2 (February 1992)
is also possible that the weakness in PMDM is caused
by a primary or secondary defect in energy utilization.
P-3 1 magnetic resonance spectroscopy (MRS)
is a noninvasive technique that allows measurement of
several metabolites and indices important in muscle
contraction, such as phosphocreatine (PCr), inorganic
phosphate (Pi), ATP, and intramuscular pH (3,4). By
observing resting values for these indices and their
changes with exercise, it may be possible to draw
conclusions about the efficiency and use of the glycolytic and oxidative pathways. The purpose of the
present study was to use P-31 MRS results obtained
before, during, and after exercise to infer changes in
metabolic pathways that might suggest an underlying
abnormality in energy utilization among patients with
PM/DM.
PATIENTS AND METHODS
Study population. Patients with acute PM/DM, patients with treated PMDM, and a normal control group were
studied at rest and with exercise. All patients had definite
polymyositis or dermatomyositis as defined by the criteria of
Bohan and Peter (5). Acute PM/DM was defined as active
disease treated with corticosteroids for <72 hours. Treated
PM/DM was defined as clinically and chemically quiescent
disease (mean f SEM duration 3.8 2 1.7 years). One patient
in the acute PM/DM group and 1 patient in the treated
PM/DM group had polymyositis; the others had dermatomyositis. The mean age in the normal control group was similar
to that in the 2 PM/DM groups. Twelve patients (7 with acute
PM/DM, 5 with treated P m M ) and 10 controls were
studied at rest, and 11 patients (6 with acute PMDM, 5 with
treated PM/DM) and 7 controls were studied with exercise.
Exercise regimen. After informed consent was obtained, the patient or control subject was positioned within
the magnet bore. The P-31 surface coil was strapped to the
quadriceps muscle approximately halfway between the in-
NEWMAN AND KURLAND
200
ACUTE
Table 1. Resting values of inorganic phosphate/phosphocreatine
(Pi/PCr) and pH in the 3 groups studied*
Group
P;/PCr ( X Id)
PH
Acute PM/DM (n = 7)
Treated PM/DM (n = 5)
Control (n = 10)
10.4 2 1.3
7.04 -+ 0.03
7.02 f 0.01
7.05 f 0.01
7.7 2 0.5
9.6 0.7
*
* Values are the mean
dermatomyositis.
v
a-
9.
PRI
Figure 1. Representative P-31 magnetic resonance spectra from a
control subject and a patient with acute polymyositis/dermatornyositis. Upper spectra were obtained after the fourth set of exercises
(EX); lower spectra were obtained at baseline (BASE [resting]). Pi
= inorganic phosphate; PCR = phosphocreatine; PPM = parts per
million. See Patients and Methods for acquisition and processing
conditions.
guinal ligament and the superior border of the patella.
Baseline (resting) scans were performed (see below), after
which the subject performed 4 sets of 30 leg lifts (at a rate of
1 lift per 2 seconds). The leg lifts were accomplished by
flexing the hip to -30" with the knee extended. Each set
(lasting 1 minute) was followed by a 30-second scan period.
Restinghecovery scans were performed at 30 seconds, 5 %
minutes, and 13 minutes after the fourth set of leg lifts; thus,
measurements were obtained at a total of 8 time points (1
baseline, 4 exercise, 3 recovery) for each study.
Spectroscopy. Unlocalized P-31 MR spectra were
obtained at 1.5 Tesla on a GE Signa system with use of a
Medical Advances (Milwaukee, WI) 7' transmit/Y receive
surface coil. The following scan parameters were used:
repetition time = 1.5 seconds; spectral width = 4 kHz;
RESULTS
Data obtained with subjects at rest. Table 1
illustrates that the ratio of Pi to PCr at rest tended to be
higher in patients with acute P M D M and lower in
patients with treated PM/DM, when compared with
controls, although the differences were not statistically
significant. The intramuscular pH was virtually identical in the 3 groups.
-I!
ij&
.75
.751
a
:
n
SEM. PM/DM = polymyositis/
averages = 100 (baseline, restinghecovery scans) or 20
(post-exercise scans). Field homogeneity and radiofrequency transmitter power were optimized on phantoms prior
to the examination and on the PCr line of a slice-selected
region (30 mm thick) in the quadriceps for each subject.
Fourier transform spectra were processed (without
knowledge of the subject's status) on a Sun Sparcstationl
workstation, by use of NMRi (Syracuse, NY) software.
Phasing and piecewise integration were carried out by means
of semiautomated routines to minimize operator bias, as was
the piecewise baseline deconvolution (6) used to eliminate
broad baseline humps. Mild filtering (2 Hz exponential line
broadening) was used on each spectrum. Integrals for regions corresponding to Pi, PCr, and ATP lines were used as
a database for statistical analysis by STATA software (Computing Resource Center, Santa Monica, CA). Representative
P-3 1 spectra for a control subject and for a subject with acute
PM/DM are shown in Figure 1.
.u
.v
-5
2
1
=
n
n
0
1
2
3
4
5
ACUTE
6
7
8
1
2
3
4
5
TAEATED
6
7
0
1
2
3
4
5
6
7
0
CONTROL
Figure 2. Changes in the ratio of inorganic phosphate to phosphocreatine (PilPCr ratio) with exercise, in patients with
acute polymyositis/dermatomyositis(PM/DM), patients with treated PMIDM, and controls. Point I represents baseline,
points 2-5 represent spectra obtained during the exercise protocol, and points fj-8 represent the recovery period. Data are
represented as box-and-whisker plots. The box is limited by the first and third quartiles (twenty-fifth and seventy-fifth
percentiles). The horizontal line within the box represents the median (fiftieth percentile). The verticle lines (whiskers)
extend to the limits of the data, excluding outliers (values greater than I .5 times the interquartile range [third quartile minus
first quartile]), which are represented by a circle.
P-31 MRS AND EXERCISE IN PWDM
2
.
Pi
I
-5
20 1
0
1
2
3
4
5
6
7
0
1
2
3
0
4
5
6
7
1
8
2
3
TREATED
ACUTE
4
5
6
7
8
6
7
0
6
7
0
CONTROL
1.5 7
1
1.5
1.51
Pcr
-1
1
2
3
4
5
6
7
6
1
2
3
4
5
6
7
0
1
2
3
TREATED
ACUTE
4
5
CONTROL
0
1e5
1
-51
0
1
2
3
4
5
6
7
0
1
2
ACUTE
3
4
5
TREATED
6
7
8
.
1
l
2
3
4
5
CONTROL
Figure 3. Relative changes in inorganic phosphate (Pi), phosphocreatine (Pcr), and &ATP levels with exercise, in patients
with acute polymyositis/dermatomyositis (PM/DM), patients with treated PM/DM, and controls. Point 1 represents
baseline, points 2-5 represent spectra obtained during the exercise protocol, and points 6-8 represent the recovery period.
Values are ratios compared with baseline (point 1; value = 1). Data are represented as box-and-whisker plots. The box is
limited by the first and third quartiles (twenty-fifth and seventy-fifth percentiles). The horizontal line with the box
represents the median (fiftieth percentile). The vertical lines (whiskers) extend to the limits of the data, excluding outliers
(values greater than 1.5 times the interquartile range [third quartile minus first quartile]), which are represented by a circle.
Data obtained immediately after exercise. As
seen in Figure 2, the acute PM/DM group had an early,
substantial increase in the Pi/PCr ratio with exercise, and
a rapid recovery period. The treated PM/DM group
exhibited a similar rise in the Pi/PCr value, although it
was slightly delayed. The Pi/PCr ratio in the control
group changed very little with exercise (Figure 2).
To better understand the contributions of individual metabolites, changes in the Pi, PCr, and ATP
intensities with exercise, relative to those at rest, were
examined (Figure 3). The Pi value rose with exercise in
both the acute PM/DM and the treated PM/DM
groups. However, the PCr value changed very little in
these 2 groups during exercise, whereas a marked
decrease of PCr would normally be expected as the Pi
is rising. Finally, ATP levels (as measured by PATP)
fell dramatically in response to exercise in the acute
PM/DM and treated PM/DM groups.
DISCUSSION
P-3 1 magnetic resonance spectroscopy is a noninvasive procedure that allows in vivo testing of the
glycolytic and oxidative pathways of energy utilization
at rest and during muscle contraction. With this technique, intramuscular phosphocreatine, inorganic phosphate, ATP, and pH levels can be measured and their
change with exercise monitored. The Pi/PCr ratio
provides an inverse measure of energy reserve: The
lower the ratio, the more energy is available for muscle
contraction.
Because of its unique capabilities, P-31 MRS
has been used to study a variety of myopathic states,
including mitochondria1 diseases, dystrophies, and
metabolic myopathies (3,4,7). However, very little is
known about the use of this technique in polymyositis
and dermatomyositis. Fraser et a1 studied polymyosi-
NEWMAN AND KURLAND
tis, dermatomyositis, and inclusion body myositis patients at rest (8). They found that Pi/PCr levels seemed
to correlate with quantitative disease activity scores.
PM patients had higher resting Pi/PCr levels compared
with DM patients and controls. In a study of magnetic
resonance imaging and P-31 MRS in 4 patients with
DM, Park and colleagues found significantly higher
resting PJPCr values in the patients compared with
controls (9).
Our data indicate only a slightly higher resting
Pi/PCr value in acute PM/DM patients compared with
controls. Differences in the patient groups studied may
help to account for the differing results among studies.
Our acute PMDM group consisted of patients who
were essentially untreated (6 DM, 1 PM), whereas
Park et a1 studied patients with established disease
who were receiving ongoing treatment. One of their
patients, who had a recent diagnosis of DM (similar to
the patients in our acute PM/DM group), had a PCr
level close to those in their control group.
The weakness seen in patients with PM and DM
does not correlate well with other measures of disease
activity, such as CPK values and degree of inflammation on muscle biopsy (1,2). Sampling error during
muscle biopsy might explain the differences in results
between muscle histopathologic studies and clinical
strength testing. However, another possibility is that
weakness in patients with PM/DM is due to an underlying metabolic defect in muscle energy utilization.
Chowdhury et al (10) studied glucose utilization and
enzyme activity in a murine model of polymyositis
(CD-1 Swiss mice infected with coxsackievirus Bl).
They found reduced myoadenylate deaminase (MAD)
and myophosphorylase activity compared with controls. Further analysis of the increased C 0 2 production seen in this model supported utilization of the
pentose phosphate shunt, which is normally not utilized in muscle to any extent. Finally, recent work by
Sabina and colleagues (11) suggests that levels of
MAD activity and MAD transcripts are reduced in
some patients with PM.
Our exercise data also support the notion of an
underlying defect in energy utilization in PM/DM.
First, a heightened response of Pi/PCr during exercise
was seen not only in patients with acute untreated
PM/DM, but also in patients who had been diagnosed
several years earlier and were considered to have
clinically inactive disease. Second, in both the acute
PM/DM and the treated PM/DM groups, ATP levels
declined during exercise, despite the presence of a
strong PCr signal. There are several possible explana-
tions for this finding. From a macroscopic perspective,
it may be that there is preferential utilization of type
IIB (glycolytic) fibers, which would rapidly deplete
their PCr stores and then utilize ATP. The lack of
oxidative capacity in these fibers would prevent maintenance of ATP levels. The strong PCr signal would
then result from surrounding type I and IIA fibers,
which are not being utilized. A similar metabolic
response has been suggested in non-athletes exercising
at high work loads (12). From a microscopic perspective, a functional metabolic block at the level of the
enzyme CPK, limiting the use of PCr, might account
for the depletion of ATP in disproportion to what
would be expected. Indeed, in combination with the
postulated deficiency of MAD (1l), regeneration of
ATP would be significantly compromised.
In summary, patients with acute untreated polymyositis and dermatomyositis, as well as treated patients with chemically and clinically quiescent disease,
show a marked rise in the Pi/PCr value with exercise.
In addition, ATP levels are not preserved despite the
presence of PCr, indicating inefficient utilization of
energy substrates. Further work is needed to correlate
these abnormalities with results of quantitative
strength testing.
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82:333-338, 1989
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1986
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P-31 MRS AND EXERCISE IN PMDM
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mal energy metabolism in murine polymyositis (abstract). Arthritis Rheum 32 (suppl4):S125, 1989
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