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Department of Neurology (J.R.S.), Howard Hughes Medical Institute (B.L.B.), and Huntsman Cancer Institute (A.T.), University of Utah Medical School, Salt Lake City, Utah 84132
Address all correspondence and requests for reprints to: J. Robinson Singleton, M.D., Department of Neurology, University of Utah Medical School, Room 3R-152, 50 North Medical Drive, Salt Lake City, Utah 84132. E-mail: rob.singleton{at}hsc.utah.edu
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Abstract |
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, which, in turn, competes
with the complete PI3K heterodimer for binding at insulin receptor
substrate-1, inhibiting PI3K activation. Dexamethasone blocks
IGF-I-induced phosphorylation of Akt, a PI3K-dependent process.
Increased cellular p85 abundance, induced by either 10
µM dexamethasone or transient transfection with a plasmid
coding for p85, significantly inhibits IGF-I rescue from apoptosis
induced by mannitol, as indicated by both loss of cell viability and
increased activity of caspase-3 by fluorogenic assay. Conversely,
constitutively active PI3K inhibits death induced by mannitol, even in
the presence of dexamethasone. These findings may have particular
relevance in the pathogenesis of acute steroid myopathy in critical
illness, in which catabolic glucocorticoid effects combine with acute
metabolic stressors, including sepsis, fasting, and chemical
denervation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The striking muscle atrophy and protein loss associated with AQM reflect the potent catabolic effects of glucocorticoids in synergy with other metabolic stressors in critical illness. One likely mechanism for this catabolic effect is inhibition of hormones that normally act to maintain anabolic homeostasis in skeletal muscle. Insulin-like growth factor I (IGF-I) is one of a family of hormones that have recognized proliferative and anabolic effects on skeletal muscle cells. IGF-I binds to and activates type I IGF receptor (IGF-IR) on the surface of cells (7). Intracellular signaling derived from IGF-IR activation occurs through two recognized pathways: activation of the mitogen-activated protein kinase cascade potentiates proliferation of myoblasts and satellite cells, and signaling through phosphatidylinositol 3-kinase (PI3K) is responsible for the anabolic effects of IGF-I on muscle (increased glucose uptake, protein synthesis, and inhibition of protein breakdown) (8, 9). In addition, in many cells, signaling through PI3K increases the resistance of cells to programmed cell death (10, 11).
PI3K is a heterodimer. The 85-kDa regulatory subunit (p85)
contains two Src homology-2 (SH-2) domains that allow it to bind to the
IGF-IR-associated protein insulin receptor substrate-1 (IRS-1) and
approximate the catalytic 110-kDa (p110) subunit to the cell membrane
surface, where it can initiate phosphoinositide conversion (12, 13).
Two closely related 85-kDa isoforms, p85 and p85ß, have been
characterized (14, 15). In skeletal muscle, glucocorticoid signaling
has been shown to induce transcriptional up-regulation and increased
cellular abundance of the p85 subunit (16, 17). Overabundant p85
monomer competes for IRS-1 binding with p110/p85 PI3K heterodimers,
inhibiting approximation of the p110 catalytic subunit to the membrane
surface and thus retarding PI3K activity (16). The pathogenetic
relevance of this observation to disease states associated with
endogenous or exogenous glucocorticoid excess has not been
explored.
IGF-I signaling often acts to protect cells from apoptosis due to metabolic stress (18). We hypothesize that dexamethasone contributes to myopathy in the setting of critical illness in part by inhibiting the PI3K-mediated, anabolic, and antiapoptotic effects of IGF-I. The L6 rat myoblast cell line is a recognized model for evaluation of myogenesis and response to myocyte injury (19). We have examined the response of L6 myoblasts in culture to metabolic hyperosmolar stress with mannitol, modified by IGF-I and the glucocorticoid dexamethasone in combination.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and p110 CAAX were
gifts from Dr. Julian Downward (Imperial Cancer Research Fund, London,
UK). L6 rat myoblasts were obtained from American Type Culture Collection (Manassas, VA). Monoclonal antibodies to PI3K subunit
p85 (sc-1637) and to IRS-1 (sc-559) were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA), antibodies to total
Akt and phosphorylated Akt were obtained from New England Biolabs, Inc. (Beverly, MA), CaspACE fluorometric assay kit for
caspase-3 (G3540) was purchased from Promega Corp.
(Madison, WI), and Lipofectamine reagents were obtained from Life Technologies, Inc.(Gaithersburg, MD). FCS and horse serum (HS)
were purchased from HyClone Laboratories, Inc. (Logan,
UT), and matched lot numbers were used throughout these experiments.
The PI3K inhibitor LY-294002 and the mitogen-activated protein kinase
inhibitor PD-98059 were purchased from Calbiochem (San
Diego, CA). Dexamethasone sodium phosphate was obtained through the
University of Utah in-patient pharmacy from Elkins-Sinn, Inc. (Cherry
Hills, NJ). L6 rat myoblasts were cultured at 37 C in 10% CO2 in DMEM containing 1.0 mg/ml glucose, 20% FCS, penicillin, and streptomycin. Myoblasts were passaged or used for experiments at 80% confluence and were detached from plates using 0.25% trypsin and 1 mM EDTA. To minimize apoptosis due to serum withdrawal, all experimental conditions were performed in a background of DMEM containing 1% HS.
For green fluorescence protein (GFP) counting experiments, cells were
cultured on 3.5-cm, 6-well plates on which 2 x 3 grid lines had
been etched to facilitate reproducibly identifying and following
specific cell populations longitudinally. Myoblasts in log phase growth
at 60–80% confluence were transfected with plasmid encoding GFP
behind the cytomegalovirus constitutive promoter or in separate
experiments were cotransfected with GFP plus plasmids encoding either
the PI3K p85 subunit or the p110 subunit linked to a CAAX sequence,
targeting it to the cell membrane. Transfection using Lipofectamine
yielded 1–5% efficiency. Transfected myoblasts were returned to
growth medium for a period of 16 h, then a microscope field of
GFP-positive cells was counted at 6 intersections of the grid (yielding
400–800 cells) before treating the cells with differentiation medium
containing combinations of 300 mM mannitol, 10
µM dexamethasone, and 10 nM IGF-I. For each
condition, GFP-positive cells at established grid sites were recounted
at 12, 24, and 48 h after treatment. All GFP experiments were
counted and tabulated in a blinded fashion after treatment conditions
were independently randomized and coded.
In experiments to determine the activity of caspase-3, L6 myoblasts were grown to 70% confluence in 10-cm dishes, then treated with combinations of mannitol, dexamethasone, and IGF-I. At various time points, treatment medium was collected from plates, adherent cells were washed with ice-cold PBS, then lysed with ice-cold RIPA buffer (1 x PBS, 1% Nonidet-40, 0.5% sodium deoxycholate, and 0.1% SDS with protease inhibitors: 1 mM PMSF, 1 mM Na3VO4, 10 µg/ml aprotinin, and 0.5 µg/ml leupeptin) for 15 min. Detached cells in the medium were isolated by centrifugation, washed once with PBS, then combined with adherent cells in the lysis buffer. Lysed cells were scraped from plates with a rubber policeman and sonicated (half-power for 15 sec twice), and supernatants were separated from membrane debris by microcentrifugation 12,000 rpm for 5 min. Aliquots of cell lysates containing 75 µg protein were assayed in triplicate for caspase-3 activity using the kit according to the manufacturer’s instructions.
Immunoblotting for total p85, total Akt, and phospho-Akt was
performed using modification of methods previously described (10). Cell
lysates were collected as described for the caspase-3 assay. For each
condition, equal amounts of lysate protein (usually 75 µg) were
separated on a 12% SDS-polyacrylamide minigel along with mol wt
markers, transblotted to a polyvinylidene difluoride membrane, blocked
in 1x Tris-buffered saline with Tween-20 with 5% milk
overnight, and blotted with primary and appropriate secondary
antibodies at concentrations recommended by the manufacturers. Blots
were evaluated using enhanced chemiluminescence according to the
manufacturer’s manual (Amersham Pharmacia Biotech,
Arlington Heights, IL).
Statistical analysis for differences in GFP-positive cell viability and caspase-3 activity, were performed using one-tailed Student’s t test. Unless otherwise stated in the figure legends, graphs represent the mean ± SEM for three to six independent determinations for each data point.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In contrast,
control GFP-positive myoblasts treated with 1% HS alone slowly
increase in number over 48 h, indicating some continued
proliferation.
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). Caspase-3 is one of a family of proteases whose activation
by proteolytic cleavage is recognized as a critical initiating step in
the irreversible propagation of the apoptosis pathway. At doses above
30 mM, mannitol induces activation of caspase-3, which
precedes loss of L6 viability by GFP cell counting.
To demonstrate that glucocorticoids induce overexpression and
intracellular accumulation of the p85 subunit of PI3K in our system,
we performed Western blot analysis of L6 cell lysates 6 h after
treatment with increasing doses of dexamethasone (Fig. 2A). Probing with mouse monoclonal
antibody directed at p85 demonstrates a dose-dependent increase in
cellular p85 abundance above baseline, beginning with 100
nM dexamethasone and reaching maximal abundance at 30
µM.
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by dexamethasone does not in itself affect L6
myocyte viability. As shown in Fig. 2B, GFP-positive myocytes treated
with dexamethasone for 48 h show no significant death compared
with those treated with 1% HS alone at dexamethasone doses below 100
µM. Dexamethasone has been reported to potentiate the
proliferative effects of IGF-I by increasing phosphorylation of IRS-1,
increasing signaling through the mitogen-activated protein kinase
cascade (20). Dexamethasone treatment of L6 myocytes in the presence of
the MEK inhibitor PD-98059 did not significantly alter viability
compared with the effect of dexamethasone alone, indicating that loss
of cell viability was not being obscured by increased proliferation in
response to dexamethasone potentiation of mitogens in the serum (data
not shown).
Based on these experiments, a dexamethasone dose of 10 µM
was selected for further investigation. We found that at this dose,
dexamethasone acts to potentiate death in response to mannitol
primarily by inhibiting IGF-I signaling. Figure 3A shows GFP counting results at 24 and
48 h for L6 myocytes treated with various combinations of 300
mM mannitol, 1 µM dexamethasone, and 10
nM IGF-I. Mannitol causes a 60% loss of viability compared
with treatment with 1% HS. IGF-I exerts a potent trophic effect on
these myocytes and largely prevents the loss of cell viability in
response to mannitol. Dexamethasone does not cause cell death alone and
results in only a modest increase in cell death when added to mannitol.
However, dexamethasone significantly inhibits the ability of IGF-I to
rescue myocytes from death induced by mannitol. Caspase-3 activity
measured in L6 lysates after 12 h of treatment with these
conditions (Fig. 3B) closely mirrors the results of GFP counting.
Mannitol induced a 3-fold increase in active caspase-3 over baseline,
indicating initiation of apoptosis, an effect that IGF-I inhibits. In
the presence of dexamethasone, protection from mannitol-induced
apoptosis by IGF-I was inhibited.
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). Pretreatment
of myoblasts with dexamethasone for 5 h before addition of IGF-I
suppresses Akt phosphorylation by IGF-I. In contrast, dexamethasone
treatment concurrently with or 1 h before IGF-I addition does not
suppress IGF-I-mediated Akt phosphorylation, consistent with a
requirement for de novo transcription and intracellular
accumulation of p85. Dexamethasone alone did not alter Akt
phosphorylation, and none of the conditions affected total Akt
abundance.
Experiments using constitutively active or dominant negative PI3K
subunits were performed to further evaluate disruption of IGF-I
signaling through PI3K. L6 myoblasts were cotransfected with GFP plus
either a plasmid coding for the p85 subunit behind a constitutive
cytomegalovirus promoter or a plasmid coding for the catalytic 110-kDa
subunit to which a CAAX sequence was appended to localize the subunit
to the plasma membrane. As no interaction with the p85 subunit or
with IRS-I was necessary for activation, transfection with p110 CAAX
produced a constitutively active PI3K.
The results of GFP counting after treatment of transfected myocytes
with mannitol and/or IGF-I are shown in Fig. 4. Overexpression of p85 by
transfection recapitulated the effect of dexamethasone (Fig. 4A). IGF-I
inhibited myocyte death induced by mannitol. However, in cells
overexpressing p85, this inhibitory effect was retarded. In
contrast, L6 myoblasts transfected with constitutively active p110 CAAX
showed inhibition of apoptosis induced by mannitol. Significantly,
cotreatment of p110 CAAX-transfected cells with IGF-I did not further
increase rescue from mannitol-induced death, suggesting that the
constitutively active p110 and IGF-I act through a common pathway to
mediate their antiapoptotic effects. Cotreatment of L6 cells
transiently transfected with p110 CAAX with 10 µM
dexamethasone and 300 mM mannitol did not decrease their
viability compared with that of similarly transfected myoblasts treated
with mannitol alone (Fig. 4B). This result is consistent with the
concept that constitutively active p110 acts downstream of the
inhibitory effects of increased IRS-1 occupancy by p85 monomer
induced by dexamethasone.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We find that dexamethasone increases the L6 myocyte abundance of the
regulatory p85 subunit of PI3K severalfold, as measured by
immunoblotting, in agreement with previous studies (16, 17). Giorgiono
et al. showed that dexamethasone induced a dramatic increase
in undimerized p85 subunit occupancy on IRS-1, with consequent
reduction of IRS-1-associated p110 (by immunoblotting) and PI3K
activity (by metabolic labeling experiments) (16). Undimerized p85
may exert inhibitory effects on PI3K activation out of proportion to
its stochiometric excess compared with the p110/p85 heterodimer. p85
interacts with IRS-1 at sites distinguished by phosphorylated tyrosine
residues (26). Free p85 has been reported to bind to these
tyrosine-phosphorylated motifs more avidly than do p110/p85
heterodimers, magnifying the IRS-1 occupancy of a modest p85 monomer
excess (27, 28). Moreover, phosphoinositol 3,4,5-triphosphate, the
product of PI3K phosphoconversion, may act to displace PI3K from IRS-1
in a highly localized feedback inhibition loop by interacting with the
p85 SH2 domain (29). Catalytically inactive p85 might thus enjoy
relatively prolonged occupancy on IRS-1 while at the same time
preferentially binding to IRS-1 sites abandoned by more rapidly cycling
p85/p110 heterodimers.
Our results indicate that this dexamethasone-induced inhibition of PI3K
signaling has dire functional consequences for the ability of IGF-I to
protect myocytes from apoptosis induced by metabolic stress. Increased
p85 abundance, induced by either dexamethasone or transient
transfection with a plasmid coding for p85, inhibits IGF-I rescue
from apoptosis, as indicated by both loss of cell viability and
increased activity of caspase-3. Three of our results directly support
the concept that dexamethasone’s effect on L6 myoblasts is mediated
specifically by inhibition of PI3K. 1) Dexamethasone ameliorates
IGF-I-induced Akt phosphorylation. The time course of this inhibition
over 5 h is consistent with a requirement for new p85 gene
transcription and translation in response to dexamethasone. 2)
Introduction of PI3K catalytic subunit p110 made constitutively active
by a cell membrane localization sequence prevents dexamethasone effects
on L6 viability. 3) Dexamethasone alone does not induce myoblast death
even at suprapharmacological doses.
Our results support the concept that dexamethasone, by virtue of its competitive mechanism, is a relatively weak and incomplete inhibitor of PI3K. In contrast to LY294002, dexamethasone pretreatment only partially inhibits Akt phosphorylation by IGF-I. Similarly, we find that dexamethasone alone does not induce L6 myoblast death even at suprapharmacological doses. Potent inhibitors of PI3K, including LY294002 and the hydroxymethylglutaryl coenzyme A inhibitor simvastatin, have been reported to directly decrease viability of L6 myoblasts (19). Taken together, these observations suggest that dexamethasone instead plays a permissive role, by inhibiting the PI3K-mediated antiapoptotic effects of IGF-I in response to a separate metabolic stressor, hyperosmolar injury with mannitol.
Myopathic damage due to glucocorticoids forms a clinical and pathological spectrum, from the subtle weakness, mild myosin loss, and type II fiber atrophy associated with chronic, moderate dose steroid use to the severe paresis, sarcomeric disarray, profound atrophy, and myotube lysis associated with AQM (4, 5, 6, 30, 31). AQM pathogenesis is distinguished from chronic steroid myopathy not only by the large doses of glucocorticoid involved, but by synergism with catabolic effects of other metabolic stressors confronting the critically ill, including sepsis, starvation, inactivity, and chemical denervation. Many of these metabolic concomitants of critical illness have been shown to decrease signaling at steps along the GH-IGF-I anabolic pathway in skeletal muscle.
Our results define one mechanism for inhibition of IGF signaling
downstream of IGF-IR binding. However, other postreceptor defects in
IGF signaling associated with critical illness probably exist. Sepsis
is characterized by overexpression of the immune cytokine tumor
necrosis factor- (TNF). Exogenous TNF induces cachexia in
experimental animals, and in L6 myoblasts it inhibits muscle protein
synthesis induced by IGF-I in a dose-dependent manner (32), suggesting
that TNF may inhibit IGF signaling at or beyond the level of IGF-IR
activation on skeletal muscle. Similarly, inactivity after hindlimb
unweighting in rats results in a transient decrease in muscle
sensitivity to both IGF-I and insulin (33), suggesting inhibition of
intracellular signal transduction enzymes common to both pathways.
Metabolic stressors most often affect serum IGF abundance. IGF-I messenger RNA and serum IGF-I decrease during acute and chronic fasting, and rebound with refeeding (34). Sepsis is also associated with decreased production and serum concentration of IGF-I (35). Recent experiments indicate that high dose methylprednisolone or triamcinolone reduces IGF-I and IGF-II expression in the rat liver and in diaphragm and gastrocnemius muscles (36), suggesting that PI3K inhibition may not be the only effect of glucocorticoids on IGF signaling in skeletal muscle. Overall, it is plausible that additive or synergistic effects of IGF-I inhibition due to multiple metabolic stressors contribute to the severe protein catabolism and muscle apoptosis observed in AQM.
These results do not provide a direct explanation for the profound loss of strength that defines AQM clinically. Although severe myotubular necrosis has been reported in AQM, in most patients myosin loss and sarcomeric disarray, suggestive of catabolic effects on muscle, are accompanied by only modest evidence of myotubular death (5, 6). Murine models of AQM combining high dose iv steroids with acute focal denervation confirm the observation in human patients of electrical inexcitability of many myofibers in this condition (37, 38). Although the steroid/denervation model does not reproduce the systemic stressors induced in the critically ill patient by sepsis, starvation, and organ failure, this model predicts that weakness in AQM results in large part from reversible changes in sodium and chloride channels that inhibit depolarization (38). The mechanism by which steroids may induce these changes in myofiber membrane conductance is not known.
In summary, we suggest that glucocorticoids antagonize the trophic effects of IGF-I signaling through PI3K and may synergize with other stressors inhibiting IGF-I signaling to induce myopathy in the critically ill. Our results indicate that in severe cases of steroid-associated myopathy, apoptosis may also occur as a result of cumulative IGF-I inhibition. These results have uncertain implications for the use of IGF-I in the treatment or prophylaxis of AQM. Intravenous treatment with IGF-I has recently been shown to prevent muscle atrophy due to chronic administration of glucocorticoids in rats (39). However, our results suggest that reversing the catabolic or apoptotic effects of glucocorticoids on muscle in the setting of acute critical illness may be difficult with supplementation of IGF-I.
Received December 10, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, a subunit of phosphatidylinositol
3-kinase, and its homologue p85ß. Oncogene 7:789–793[Medline]
expression in response to dexamethasone is
associated with inhibition of insulin-like growth factor-I stimulated
phosphatidylinositol 3-kinase activity in cultured muscle cells. J
Biol Chem 272:7455–7463 inhibits serum
and insulin-like growth factor-I stimulated protein synthesis.
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