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Cytokine expression in the muscle of HIV-infected patients Evidence for interleukin-1 accumulation in mitochondria of AZT fibers.

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Cytohne Expression in the Muscle of
HIV-infected Patients: Evidence for
Interlekn-la Accumulation in
Mitochondria of AZT Fibers
R. K. Gherardi, MD," A. Florea-Strat, MD," G. Fromont, MD,P F. Poron,"
J-C. Sabourin, MD," and J. Authier, MD"
To evaluate the possible role of cytokines in human immunodeficiency virus (H1V)-associated muscular disorders, we
performed immunocytochemistry for interleukin-la, - 1p, and -6 and tumor necrosis factor-@on frozen muscle biopsy
specimens from HIV-infected patients with various myopathies (HIV polymyositis in 5, HIV-wasting syndrome in 5 ,
tidovudine myopathy in 10)and from seronegative individuals (normal muscle in 2, mitochondrial cytopathies in 10).
The HIV-infected patients showed positive reactivities in vessels (interleukin-1) and in inflammatory cells (mainly
interleukin- 1 and tumor necrosis factor-a), including perivascular hemosiderin-laden macrophages in 5 patients. In
zidovudine myopathy, a majority of AZT fibers (i.e., ragged-red fibers with marked myofibrillar changes) showed
mild to marked expression of interleukin-1. Expression of interleukin-1 in the other mitochondrial myopathies was
much weaker. Interleukin-lp messenger RNA was demonstrated in muscle fibers by in situ hybridization, implying
that interleukin- 1 was produced in muscle cells. Immunoelectron microscopy showed that interleukin-la was mainly
bound to mitochondrial membranes in AZT fibers. Proinflammatory and destructive effects of the studied cytokines
might be responsible for several myopathological changes observed in HIV-infected patients, including inflammation
and hemosiderin deposits in muscle tissue, and prominent myofibrillar breakdown in AZT fibers.
Gherardi RK, Florea-Strat A, Fromont G, Poron F, Sabourin J-C, Authier J. Cytokine expression
in the muscle of HIV-infected patients: evidence for interleukin-la accumulation
in mitochondria of AZT fibers. Ann Neurol 1994;36:752-758
are atrophic ragged-red fibers with marked myofibrillar
alterations E5-91; (iii) the HIV-wasting syndrome [lo},
a cachectic myopathy associated with systemic release
of noxious cytolunes [I 13; and (iv) various opportunistic and neoplastic disorders involving the muscle 112,
It is currently believed that cytokines play a central
role in human immunodeficiency virus (HIV) infection
and mediate B-cell hyperactivity, fever, and tissue destruction, which are prominent symptoms of acquired
immunodeficiency syndrome (AIDS) I11. Infection by
HIV induces macrophage activation with increased
monolune release, and elevated circulating levels of
interleukin (1L)-1, tumor necrosis factor (TNF)-a, and
IL-6 have been observed in patients with AIDS El}.
Immunocytochemical studies on brain [2} and spinal
cord [ 3 } tissues have shown increased cytokine expression, suggesting a role of local production of cytokines
in the genesis of HIV encephalopathy and vacuolar
myelopathy .
Muscular disorders in HIV-infected patients mainly
include (i) WIV-associated myopathy that usually fulfills the criteria for polymyositis 141; (ii) zidovudine
(AZT) myopathy, a mitochondrial myopathy characterized by the presence of so-called AZT fibers, which
In the present study we evaluated the expression
of IL-la, IL-lp, TNF-a, and IL-6 in muscle biopsy
specimens from HIV-infected patients with muscular
disorders, using immunocytochemistry. Positive reactivities, mainly for IL-1, were observed in vessels, inflammatory cells, and AZT fibers. Messenger RNA
(mRNA) in situ hybridization showed that IL-lP was
produced by AZT fibers, and IL-la appeared bound
to mitochondrial membranes as shown by immunoelectron microscopy. As IL-1 produces proteolysis that affects myofibrillar proteins, our results may indicate that
the prominent myofibrillar breakdown in AZT fibers
results from proteolytic effects of IL-1.
From the *Department of Pathology (Neuropathology), Hdpital
Henri Mondor, Crgteil, and the +Service Central d'hnatomie et de
Cytologie Pathologiques, Hdpital Necker, Paris, France.
Address correspondence to Dr Gherardi, Departement de Pathologie (Neuropathologie), Hdpital Henri Mondor, 94010 Crkteil,
Received Oct 13, 1993, and in revised form Jan 5 , Feb 14, and Apr
13, 1994. Accepted for publication Apr 15, 1994.
752 Copyright 0 1994 by the American Neurological Association
Patients and Methods
W e studied muscle biopsy specimens from HIV-infected patients with the following muscular disorders: 10 patients with
typical zidovudine-induced mitochondrial myopathy, 5 with
HIV-associated myopathy not treated by zidovudine, and 5
with the HIV-wasting syndrome. The diagnostic criteria we
used have been reported [8, 10): Zidovudine myopathy was
documented in zidovudine recipients with myopathy by the
presence of atrophic ragged-red fibers with myofilamentous
abnormalities including cytoplasmic body formation; the
HIV-associated myopathy was recognized when the immunohistological profile of polymyositis was present, that is,
endomysial infiltrates of CD8' cells with sarcolemmal expression of major histocompatibility complex (MHC) class I
antigens in a majority of muscle fibers; and the HIV-wasting
syndrome was defined by involuntary weight loss ( > l o % of
baseline body weight) plus either chronic diarrhea (for 30
days or longer) or chronic weakness and documented fever
(for 30 days or longer), in the absence of a concurrent illness
or condition other than H I V infection that could explain the
findings. None of the patients with HIV-wasting syndrome
had partial cytochrome c oxidase deficiency attributable to
zidovudine IS). Patients with neurogenic muscle atrophy or
necrotizing vasculitis were excluded from the study.
Muscle biopsy specimens from 12 patients seronegative
for H I V were studied for comparison: 2 had normal muscle
biopsy specimens and 10 had genetically induced mitochondrial cytopathy (myoclonus epilepsy with ragged red fibers
in 3 , mitochondrial cardiomyopathy in 1, Leber's hereditary
optic neuropathy in 1, Kearns-Sayre syndrome in 2, chronic
progressive external ophthalmoplegia in 1, and mitochondrial
encephalomyopathy, lactic acidosis, and strokelike episodes
in 2).
Serial 8-pn-thick cross sections of frozen muscle biopsy
specimens were stained with conventional dyes (hematoxylineosin [H&E) Gomori, and Masson trichromes) and were
processed for NADH-tetrazolium reductase, succinate dehydrogenase, and cytochrome c oxidase histochemical reactions.
Immunocytochemistry was performed using an immunoalkaline phosphatase assay (APAAP) to identify T8 lymphocytes (CD8: Leu-Za), T 4 lymphocytes and macrophages
(CD4: Leu-3), macrophages (CD14: Leu-M3), and MHC-I1
(Becton Dickinson, Mountain View, CA) and MHC-I (Dakopatts, Glostrup, Denmark) antigens. Tissue expression of cytokines was tested using APAAP on frozen sections with
antibodies raised against IL-la, IL-1P (Genzyme, Cambridge,
MA), TNF-a (gift from J. M. Cavaillon, Institut Pasteur,
Paris, France), and IL-6 (Boehringer Mannheim, Germany).
Cytokine expression was evaluated by two pathologists
(R. K. G . and A. F.-S.) and quoted as absent, mild, moderate,
or marked (0 to + + + ) in each cell type in muscle tissue.
In situ hybridization was performed on frozen tissue from
2 patients with zidovudine myopathy, using an antisense 35Slabeled riboprobe recognizing the coding sequences of the
IL-lP mRNA. This probe has been assessed on lymph node
tissue [14]. Sense probes used as controls gave no signals.
The immunoelectron microscopy was performed on 200-
pm-thick fragments of frozen muscle tissue from a patient
with zidovudine myopathy, using the anti-IL-la antibody
and a horseradish peroxidase-labeled goat anti-mouse IgG
antibody (Dakopatts), according to a method previously described [l5]. The same procedure with omission of the antiIL-la antibody was used as a control.
No staining was observed with anticytokine antibodies
in normal muscle specimens, except for positive reactivities for IL-la and IL-lP in the sarcoplasmic postsynaptic domain of neuromuscular junctions (data not
shown). Similar positive reactivities were observed in
diseased muscles and were excluded from the evaluation.
In diseased muscles, expressions of cytokines were
first analyzed in relation with the tissue structures. Cytokine expression was observed in vessels, mononuclear cells, and muscle fibers (Figs 1-3). Mononuclear inflammatory cells, whenever present, expressed IL-la, IL-lP, and TNF-a, and much less often,
IL-6. In 5 patients (2 with zidovudine myopathy and 3
with polymyositis), abundant iron pigment deposits
were found in endomysial macrophages. Some of these
macrophages expressed IL-1 and TNF-a (data not
shown). Vessels were positive for IL-lP in 19 of 20
HIV-infected patients and in 6 of 10 seronegative patients with mitochondrial cytopathies. Positivity was
observed both in endothelial cells of capillaries and
venules and in arterial smooth muscle fibers. Muscle
fibers showed mild to strong expression of IL-la and
IL-lP in 13 of 20 HIV-infected patients and 8 of 10
seronegative patients with mitochondrial cytopathies.
Expression of cytokines was also analyzed in relation
to the disease states. In the HIV-wasting syndrome,
the only positive cytokine found was IL-lP in vessels
( 5 / 5 ) , aside from slight activity in muscle fibers in 1
patient. In patients with HIV polymyositis the different cytokines were expressed in endomysial inflammatory infiltrates and in mononuclear cells at the level of
partial invasion of muscle fibers. These patients also
showed IL-1P in vessels (4/5)and occasionally, slight
expression of IL-1 in muscle fibers (2/5).
Strong IL-1 expression in muscle fibers was a distinctive feature of zidovudine myopathy: IL- la activity was
found in AZT fibers in all patients and IL-1P in 9 of 10.
The positive reactions appeared in a reticular pattern in
the cytoplasm, greatest in subsarcolemmal areas (Fig
4). Positive fibers were atrophic and showed vesicular
nuclei, myofibrillar alterations, and dark staining on
oxidative enzymatic reactions. Not all atrophic fibers
with reactive nuclei showed a positive reaction for IL-1.
A large majority of IL-1-positive fibers were not surrounded by macrophages, as assessed by serial sectioning. Mitochondrial cytopathies evaluated for comparison showed mild positive reactivity for IL-la in
occasional ragged-red fibers. In situ hybridization de-
Gherardi et al: Cytokines in Muscle During H I V Infection
case 1
case 2
+ case 3
case 5
+ case 3
a case 4
* o
case 1
o case 2
X case 5
0 0 . .
* + o o
+ I
case 6
o case 7
1 case 1
+ A
+ case 3
A case 4
I case 5
x x
case 2
case 8
m case
I * .
0 . 1 .
. + I +
x x
A case 9
I . .
0 0
* I
Fig I . Degree of expression of interleukins (IL; IL-1 a, IL-1p,
and IL-6) and tumor necrosis factor-a (TNF) in muscle biopsy
specimens from patients with (A) HIV polymyositis and (B) the
HIV-wasting syndrome.
754 Annals of Neurology Vol 36
No 5
Fig 2. Degree of expression of interleukins (IL; IL-la, IL-Ip,
and IL-6) and tumor necrosis factor-a (TNF) i n muscle biopsy
specimens from patients with zidovudine myopathy 1 (A)
and 2 (B).
November 1994
A Cardiomyop.
n o
+ o
+ . 0 0
A M + +
0 0 0 0
+ + * +
X . X .
Fi g 3. Degree of expression of interleukins (IL; IL-la, IL-lp,
and 1L-6) and tumor necrosis factor-a (TNF) in muscle biopsy
specimens from seronegative patients with mitochondrial cytopathies 1 (A)and 2 CB). MERRF = myvclonus epilepsy with ragged-red fibers; KSS = Kearns-Sayre .syndrome; CPEO = chronic
progressive external ophthalmnplegia; MELAS = mitochondrial
encephalomyopathy, lactic acidnsis, and strokelike episodes.
tected IL-lP mRNA in atrophic muscle fibers (Fig 5 ) .
Immunoelectron microscopy showed a strong peroxidase reaction in mitochondria of atrophic fibers with
marked myofibrillar loss and cytoplasmic body formation (Fig 6A). In these fibers, all mitochondria were
stained at the level of their outer and inner membranes
with labeling of residual cristae (Fig 6B). In normalappearing muscle fibers, mitochondria were not or
were very slightly stained. lmmunolabeling of the
plasma membrane was observed in both atrophic and
normal-appearing muscle fibers.
In the present study we found strong cytokine expression in muscle biopsy specimens from I-IIV-infected
patients with muscular symptoms. It mainly included
IL-lP reactivity in vascular structures; IL-la, IL-1P,
and TNF-a reactivities in mononuclear inflammatory
cells; and IL-la and IL-lP reactivities in zidovudineinduced ragged-red fibers.
Expression of IL-16 in endothelial cells and arterial
smooth muscle cells was similar in the three types of
muscle disorders investigated. Vessels may produce
IL-1 under various stimuli in vitro and in vivo, and
autocrine and paracrine actions of IL-1 within vessel
walls have been described [lb]. Vascular expression of
IL-I was previously observed in the central nervous
system of patients with AIDS, and was thought to reflect a relative state of nonspecific “immune activation”
associated with HIV infection 121. The proinflammatory effects of cytokines on endothelial cells may play
a role in vascular inflammation C17, 181, and a possible
implication of IL- 1 release in the pathogenesis of HIVassociated microvascular changes observed in skeletal
muscle [19, 201 can be hypothesized. IL-1 and TNF-a
were found in some perivascular hemosiderin-laden
macrophages in 5 patients. Hemosiderin deposits are
frequently observed in endomysial macrophages and
atrophic muscle fibers of patients with AIDS [19, 211.
They may be associated with changes in the microcirculation, the presence of erythrophagocytosis, and hyperferritinemia 1191. Interestingly, both TNF-a and IL-1
induce the expression of ferritin heavy chain in myocytes and other cells r221, and are thought to play a
role in hemophagocytosis 1231.
Vessels were the sole source of IL-1 detected in the
muscle of patients with the HIV-wasting syndrome. A
pathogenetic role for IL-1 in this syndrome has been
proposed by our group [ 111, based on the high serum
concentrations of IL-lP found in this subset of HIVinfected patients and previous data on experimental
cachexia induced by this cytokine. Our results indicate
that the HIV-wasting syndrome is not associated with
a striking production of IL-1 within muscle tissue and
may rather result from systemic release of this and
other cytokines.
Gherardi et al: Cytokines in Muscle During HIV Infection
Fig 4. Positive reactioity for interleukin IIW-1 a in ragged-red
fibers from patients u d h zidovudine myopathy. (A) The raggedred fiber is slightly atrophic and shows vesicular nuclei. A positioe reaction is not found in other atrophic fibers (immunoalkaline phosphatase assay {APAAP). X 600). IB) The reaction
product appears in a reticular pattern with subsarcolemmal reinforcement (APAAP method, x 1,400).
Fig 5 . In situ hybridization of interleukin (ILi-lP messenger
R N A on muscle tissue of a patient with zidovudine myopathy.
(a, 6, Photographs focusing on two different planes of the same
area shoui that abundant grains are observed above the sarcoplasm of an atrophic muscle fiber I X 120). Ic) Marked radiolabeling corresponding to an atrophic A Z T fiber located in the
per$ascicular region. I x 600).
756 Annals of Neurology Vol 36 No 5
November 1994
F i g 6. Immunoelectron micrograph from a patient with zidovudine myopathy studied for interhukin (lL)-lCY wactivity. (A)Peroxidase reaction is observed in a typical AZT fiber with abundant mitochondria. marked myofibrillar loss, u cytoplasmic body,
redundant basal lamina indicating atrophy, and signs of degradation. The sarcoplasmic structures of the adjacent muscle j b e r
are unstained (no counterstaining).Bar = 1 pm. (B) Peroxidase reaction is observed at the level of the outer and inner mitochondrial membranes, and, when present, along mitochondrial
cristae (no counterstainingl. Bar = 0.1 pm.
IL-la, IL-IP, and TNF-a reactivities were found in
inflammatory cells, which was in keeping with the activation of T cells and macrophages that occurs in polymyositis C24, 251. The role of cytokines in the pathogenesis of polymyositis has not been extensively
investigated. It has been suggested that expression of
MHC-I at the surface of muscle fibers, a prerequisite
for T-cell-mediated cytotoxicity, could be elicited by
interferons [24, 261. TNF-a is also capable of stimulating expression of MHC-I and MHC-I1 genes C27,281.
A role for other proinflammatory cytokines in the
pathogenesis of polymyositis may be suggested by the
previous finding of increased serum IL-la levels in patients with acute active untreated polymyositis [25}.
In patients with zidovudine myopathy, IL-la and to
a lesser extent, IL-1P were expressed in ragged-red
fibers. The detection of IL-lP mRNA in muscle fibers
was consistent with an in situ production of IL-1. By
immunoelectron microscopy, IL- 1a appeared bound to
plasma and mitochondrial membranes. Although peroxidase reaction does not have sufficient localizing ability because its lipid solubility may cause it to partition
into membranes, the labeling we observed was consistent with previous evidence that IL-la remains primarily membrane bound, whereas IL-1P is mainly secreted
in the extracellular fluid 1291. In addition, IL-1 binding
to mitochondria was reminiscent of mitochondrial accumulation of IL-lP that was observed in monocytes
stimulated by lipopolysaccharide C301. Mitochondria
from AZT fibers were selectively and markedly labeled. Sarcolemmal expression of IL-1 has been observed in normal and diseased muscle fibers E313, but
accumulation of IL-la in mitochondria of muscle fibers
has not been described.
The cause of increased IL-1 production by muscle
fibers and accumulation of IL-1 in mitochondria was
unclear in our patients. Defect in energy metabolism
of individual muscle fibers could have taken part in the
activation of IL-1 production, as IL-1 production by
skeletal muscle is stimulated by ischemia [32) and exercise 1331. Seronegative patients with mitochondrial
myopathies, however, showed less expression of IL- 1
in their muscle than did patients with zidovudine myopathy, and other factors, including HIV infection itself, were possibly implicated. It has been pointed out
that IL-1 cannot be encoded by human mitochondrial
D NA [31), and it is likely that IL-1 is produced in
cytosol and then reaches the mitochondria by diffusion
or active transfer 1341. Interestingly, it has been shown
that stress proteins facilitate the entry of other proteins
into mitochondria 1341.
Zidovudine administered to animals may induce
structural and functional mitochondrial alterations
E351. IL-1 produces proteolysis in skeletal muscle [36,
37) that affects myofibrillar proteins and is mediated
by a mechanism distinct from that of corticosteroidinduced proteolysis 1381. We suggest that the marked
myofibrillar changes within the AZT fibers could be
related to proteolytic effects of IL-1 on skeletal muscle
This work was supported by grants to Dr Gherardi from Agence
Nationale de Recherches sur le SIDA and University Paris XI1
(DRED-ER 269), and by the European Concerted Action “Neuropathology of AIDS.”
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expressions, hiv, fiber, muscle, azt, patients, evidence, interleukin, infected, cytokines, mitochondria, accumulation
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