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Original Studies |
1
Department of Medicine, University of California (K.S.P., T.P.C., K.L., L.A.-C., S.M., S.E.N., R.R.H.), San Diego, La Jolla, California 92093; Veterans Affairs Medical Center, San Diego (K.S.P., T.P.C., K.L., L.A.-C., S.M., S.E.N., R.R.H.), San Diego, California 92161; Department of Signal Transduction, Parke Davis Pharmaceutical Research (S.R.T.), Ann Arbor, Michigan 48105; Department of Biochemistry, Katholieke Universiteit Nijmogen (J.H.V.), Nijmegen, The Netherlands; and Division of Endocrinology, Beth Israel Deaconess Medical Center (A.V.-P.), Boston Massachusetts 02215
Address all correspondence and requests for reprints to: Robert R. Henry, Veterans Affairs Medical Center, San Diego (V111G), 3350 La Jolla Village Drive, San Diego, California 92161. E-mail: rrhenry{at}vapop.ucsd.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(PPAR). To determine whether
troglitazone might enhance insulin action by stimulation of PPAR
gene expression in muscle, total PPAR messenger RNA (mRNA), and
protein were determined in skeletal muscle cultures from nondiabetic
control and type II diabetic subjects before and after treatment of
cultures with troglitazone (4 days ± troglitazone, 11.5
µM). Troglitazone treatment increased PPAR mRNA levels
up to 3-fold in muscle cultures from type II diabetics (277 ± 63
to 630 ± 100 x 103 copies/µg total RNA,
P = 0.003) and in nondiabetic control subjects
(200 ± 42 to 490 ± 81, P = 0.003).
PPAR protein levels in both diabetic (4.7 ± 1.6 to 13.6
± 3.0 AU/10 µg protein, P < 0.02) and
nondiabetic cells (7.4 ± 1.0 to 12.7 ± 1.8,
P < 0.05) were also up-regulated by troglitazone
treatment. Increased PPAR was associated with stimulation of human
adipocyte lipid binding protein (ALBP) and muscle fatty acid binding
protein (mFABP) mRNA, without change in the mRNA for
glycerol-3-phosphate dehydrogenase, PPAR
, myogenin, uncoupling
protein-2, or sarcomeric 
-actin protein. In summary, we showed that
troglitazone markedly induces PPAR, ALBP, and mFABP mRNA abundance
in muscle cultures from both nondiabetic and type II diabetic subjects.
Increased expression of PPAR protein and other genes involved in
glucose and lipid metabolism in skeletal muscle may account, in part,
for the insulin sensitizing effects of troglitazone in type II
diabetes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(PPAR) (3, 4). PPAR belongs to a family of PPARs,
which are nuclear receptors comprised of three subtypes designated
PPAR, PPAR, and PPAR (4, 5, 6). PPAR exists as two isoforms,
PPAR 1, the major form present in a variety of tissues, and PPAR2
(7, 8). The precise functions of the PPAR receptors are unknown, but
they are thought to regulate lipid homeostasis, adipocyte
differentiation, and insulin action through coordinate effects on gene
transcription (4, 9, 10).
Recent studies indicate that there is a close relationship between the
capacity of various thiazolidinediones to stimulate PPAR and their
antidiabetic actions, suggesting that PPAR is the receptor for this
class of drugs (11). Recently, we and others have demonstrated that
PPAR is present in human skeletal muscle (7, 12, 13). Although
considerable evidence has accumulated about the ability of
thiazolidinediones to influence gene expression in adipocytes,
especially with regard to adipocyte differentiation (4, 10), less is
known about potential effects on gene regulation in skeletal muscle.
Toward this end, employing a human muscle cell culture system
(14), we recently reported that chronic troglitazone treatment
increases glucose transport and metabolism in type II diabetic subjects
in association with enhanced expression of the glucose transporter-1
(GLUT1) gene (15). To determine if these troglitazone-induced
improvements in glucose metabolism involve PPAR, we investigated
further the effects of troglitazone on specific gene expression in
human muscle cultures. Our results indicate that troglitazone may act
to augment insulin sensitivity by increasing expression of PPAR as
well as other genes involved in glucose and lipid metabolism, and that
skeletal muscle may also be a direct site of troglitazone action.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All supplies and reagents were obtained as described in detail previously (13, 14, 15). Troglitazone [(±)-5-[4-(6-hydroxy-2,5,7,8-tetramethylchromanyl-2-methoxy) benzyl]-2,4 thiazolidinedione] was kindly provided by Dr. Alan Saltiel at Parke-Davis Pharmaceutical (Ann Arbor, MI).
Experimental subjects
Fourteen patients with type II diabetes subjects muscle tissue
(vastus lateralis) for troglitazone treatment studies. Nine of these
patients were treated with oral antidiabetic agents (glyburide, 4;
glipizide, 1; and glipizide/metformin, 4), one with insulin, and four
with diet only. Data from 17 healthy nondiabetic control subjects is
provided for comparative purposes. Glucose tolerance was determined in
all subjects after a 75-g oral glucose tolerance test (16).
Characteristics of the study groups are summarized in Table 1
. Because obesity can have an impact on
PPAR gene expression in both muscle and adipose tissue (12, 13),
both groups were selected to be obese to limit the impact of this
variable. However, the diabetic group was somewhat more obese
(P = 0.01) and older (P = 0.001) than
the nondiabetic subjects. Fasting levels of glucose, insulin, and HbA1c
were all elevated in the type II diabetic patients compared with
nondiabetic controls (Table 1).
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Cell culture and treatment
The methods for muscle biopsy of the vastus lateralis, cell isolation, and growth have been detailed previously (14). As reported before (14), adipose cells were not present in the muscle cultures. At 80–90% confluency, growth media was changed to induce fusion to multinucleated myotubes. Troglitazone was added at 11.5 µM for 4 days beginning at the initiation of fusion. During cell fusion, the media was changed every other day. Troglitazone was dissolved in dimethyl sulfoxide (DMSO) and added to cells with media. The final concentration of DMSO did not exceed 0.05%. Control cells were treated with vehicle (0.05% DMSO) for the same time (4 days) as troglitazone-treated cells.
Quantitation of PPAR messenger RNA (mRNA) by RT-PCR
PPAR transcript levels in human skeletal muscle culture
(HSMC) cells were measured by quantitative RT-PCR using an
internal, competitive control for primer amplification. The method has
been described in detail previously (13). The ratio of each target
product/complementary RNA (cRNA) standard was plotted against the
number of copies of cRNA added to yield the equivalence point between
cRNA and target mRNA.
RNase protection assays
A solution hybridization nuclease protection method (12) was
used to distinguish PPAR1 and PPAR2 transcripts in HSMC cells and
has been described previously (17). A similar method was used to detect
uncoupling protein-2 (UCP-2) (18). Protected bands were visualized by
autoradiography and quantitated by phosphorimager analysis using
ImageQuant software (Molecular Dynamics, Sunnyvale, CA).
Northern analysis of PPAR, adipocyte lipid binding protein
(ALBP), glycerol-3-phosphate dehydrogenase (G3PDH), muscle fatty acid
binding protein (mFABP), and myogenin
Ten micrograms of total RNA was size-separated by
electrophoresis through a denaturing formaldehyde 1–1.5% agarose gel
and transferred to a nitrocellulose membrane (Nytran Plus, Schleicher &
Schuell, Keene, NH). To control for gel loading, the membranes were
stained with methylene blue, and relative intensities of the ribosomal
bands were compared quantitatively using computer imaging (NIH Image,
NIH, Bethesda, MD). DNA probes for Northern analysis were
labeled by the hexamer priming method using the Ambion DECAprime II
Random Priming Kit (Ambion, Austin, TX). The PPAR probe,
supplied by Dr. David Moller (Merck Research Labs., Rathway, NJ),
consisted of a 1.2-kb BamHI mouse complementary DNA (cDNA)
fragment from pSG5. To visualize the human ALBP mRNA, a 651-bp
EcoRI fragment from pBluescript (SK-) was utilized (kind
gift of Dr. David Bernlohr, University of Minnesota). The human G3PDH
(gift of Dr. Bruce Spiegelman, Dana-Farber Cancer Institute) probe was
an 800-bp PstI fragment from pBluescript SK-. For the mFABP
probe, a 0.5-kb EcoRI fragment of pSP6.5 containing the cDNA
for mFABP was used. The myogenin probe consisted of a 1.5-kb
EcoRI fragment from pBS. Hybridization with cDNA
[-P32 deoxycytidine triphosphate (dCTP)]-labeled
probes was carried out at 68 C in 10 mL of QuickHyb (Stratagene, San
Diego, CA) according to manufacturer’s instructions. To remove
nonspecific binding, membranes were washed twice at room temperature
first with 2x sodium citrate (SSC), 0.1% SDS buffer, and then once
with 0.2x SSC, 0.1% SDS, buffer followed by one 30-min wash at 60 C
with 0.1x SSC, 0.1% SDS buffer. After washing, membranes were exposed
to Kodak X-Omat film (Eastman Kodak, Rochester, NY) at -70 C.
Relative intensities of transcript signals were compared quantitatively
using computer imaging (NIH Image).
Analysis of protein expression
Cell protein lysates were prepared as described previously for
assay of glycogen synthase (19). Western blot analysis was as detailed
previously (14). In brief, cell sonicates were solubilized in
Laemmli’s buffer, and proteins size fractionated on 10% SDS-PAGE gels
and electrophoretically transferred to a nitrocellulose membrane.
PPAR protein was identified using a polyclonal antibody raised in
rabbits against a region common to PPAR1 and 2 (20). The
secondary antibody for PPAR was antirabbit IgG conjugated with
horseradish peroxidase, whereas a similarly conjugated antimouse IgG
was used for -actin. Proteins were visualized with SuperSubstrate
(Pierce, Rockford, IL) and exposed to autoradiograph film (XAR-5
OMAT).
Statistical analysis
Statistical significance was evaluated using Student’s t test for paired comparison. Significance was accepted at the P < 0.05 level.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA modulation with troglitazone
In nondiabetic subject samples (n = 8), control levels of
PPAR transcript were measured as 200 ± 42 x
103 copies/µg total RNA. Chronic troglitazone treatment
increased transcript levels nearly 3-fold (490 ± 81,
P = 0.003) (Fig. 1B). For
type II diabetic samples (n = 7), the control level of PPAR
transcript was 277 ± 63 x 103 copies/µg total
RNA, and increased nearly 3-fold (to 620 ± 100, P
= 0.003) following troglitazone treatment (Fig. 1C).
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isoform expression by troglitazone
Presence of the 1 and 2 isoforms of PPAR were evalulated
using an RNase protection assay. Both isoforms were expressed, but 1
abundance was 9-fold higher than 2 (90% of total; Fig. 2), as in most tissues (7, 8). In the
patient samples assayed (n = 5), both 1 (1.43 ± 0.25-fold
untreated control) and 2 (2.5 ± 0.7-fold) protected fragments
increased after troglitazone treatment. The relative expression of 1
and 2 (81 vs. 19%, respectively) was maintained in
troglitazone-treated cultures.
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protein expression
PPAR protein was observed as a band of 60–65 kDa (Fig. 3A) and was measured as 7.4 ± 1.0
AU/10 µg protein in control cells of normal subjects (n = 6).
The response to troglitazone treatment was mixed in nondiabetic cells:
four subjects increased PPAR protein levels, whereas two sets of
cultures showed no change (Fig. 3B). Combining the data, there was a
statistically significant increase (to 12.7 ± 1.8, P =
0.04) following troglitazone treatment. In diabetic cells (n = 7), the
control level of PPAR protein was 4.7 ± 1.6 and increased
nearly 5-fold to 13.6 ± 3.0 (P = 0.02) in
troglitazone-treated cultures (Fig. 3C).
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To determine whether troglitazone treatment changed levels of other mRNA transcripts whose protein products have physiological significance in muscle, semiquantitative Northern blot analysis of total RNA was performed.
mFABP mRNA increased after troglitazone treatment in both diabetic and
nondiabetic cultures (Fig. 4A). In
nondiabetic cells, mFABP transcript levels increased over control by
approximately 4-fold (P = 0.08) with treatment. The
mFABP mRNA increased by 2.5-fold ± 0.2 (P =
0.002) in diabetic muscle following troglitazone treatment. Human ALBP
was undetectable in untreated muscle cell cultures (nondiabetic
controls, n = 6; type II, n = 9), but was readily
apparent in troglitazone-treated muscle cultures (Fig. 4B). Stimulation
of ALBP transcript varied widely between patients, with no clear
difference between type II and nondiabetic subjects.
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, G3PDH, UCP-2, and
myogenin. Levels of sarcomeric-specific -actin, a structural muscle
protein, also remained constant during troglitazone treatment of
nondiabetic and muscle cell cultures. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Troglitazone acts directly on muscle in vitro to increase glucose utilization, similar to in vitro changes seen in adipose tissue (25). Human muscle cultures derived from obese type II diabetic subjects treated with chronic (4-day) troglitazone treatment consistently increased GLUT activity 3- to 4-fold independent of added insulin. This effect was associated with increases in GLUT1 transcript and protein levels (15), with little contribution from changes in total GLUT4. Similar effects of troglitazone on GLUT1 have been demonstrated in L6 myoblasts (24).
The discovery that thiazolidinediones are synthetic ligands for
PPAR, which may activate the transcriptional activity of the
receptor (3), provides a potential mechanism by which troglitazone
could regulate gene expression. PPAR controls genes involved in
lipid and glucose metabolism (4, 28, 29) as well as adipogenesis (4, 10). The predominant PPAR isoform in skeletal muscle biopsies is
1 (6, 7, 8), which is the same isoform found in human muscle cultures
(Fig. 2
). Although PPAR mRNA levels in skeletal muscle biopsies and
cultured muscle cells are lower than in adipose tissue (7, 8), the
receptor is expressed in muscle (7, 8, 12, 13) and provides a potential
target for troglitazone action.
In the current study both nondiabetic and type II diabetic skeletal
muscle cultures showed a 2- to 3-fold increase in PPAR mRNA on
exposure to troglitazone. A significant increase in PPAR protein
levels also occurred following chronic troglitazone treatment.
Troglitazone treatment is clearly capable of causing increased mRNA
levels for its target receptor, PPAR, in muscle. These results are
consistent with a feedback mechanism whereby PPAR transcript and
troglitazone could act to up-regulate PPAR protein levels in the
muscle cells of type II diabetics. Because studies have not yet
identified PPAR response elements in the PPAR promoter (4),
troglitazone effects that up-regulate PPAR expression within the
muscle cell may be indirect. However, a more detailed understanding of
PPAR regulation in human muscle cells is needed to resolve the
genetic mechanisms by which troglitazone improves skeletal muscle
insulin resistance. One important question to answer is whether
troglitazone is influencing PPAR mRNA levels by increasing gene
transcription or by stabilization of the mRNA.
Although the current results demonstrate that skeletal muscle increases
PPAR transcript levels with troglitazone treatment, this effect is
not generalized to other PPAR genes. Although PPAR is reported to be
activated by thiazolidinediones in fibroblasts and adipocytes (4) and
PPAR is present in human skeletal muscle, no significant changes in
PPAR mRNA levels occurred in troglitazone-treated cells.
Increases of mFABP mRNA in muscle cells following troglitazone
treatment is quite pronounced, as are those in ALBP levels. Because the
proteins encoded by these transcripts are responsible for binding fatty
acids and transporting them into and out of the cell (30), we postulate
that troglitazone treatment may influence cellular fatty acid transport
and alter fatty acid utilization in muscle cells, though the functional
consequences of the increases in ALBP and mFABP mRNAs need to be tested
directly. Although thiazolidinediones have adipogenic
properties, we were unable to detect any morphological changes in
cultured muscle cells beyond the appearance of the adipose-specific
ALBP mRNA after troglitazone treatment. Although fetal myocyte
precursor cells can be converted to an adipocyte phenotype following
thiazolidinedione treatment (10, 31), we were unable to detect any
changes in the differentiation state of human muscle cell cultures
following troglitazone treatment. On histological examination of muscle
cultures treated with troglitazone, the muscle phenotype was maintained
and accumulation of lipid droplets (visualized with Oil Red O staining,
data not shown) was not observed. Furthermore, no changes in mRNA
accumulation for G3PDH or UCP-2, both of which are known to be
up-regulated with adipocyte differentiation (4), occurred in treated
muscle cultures. Most importantly, expression of two specific markers
of muscle differentiation, myogenin and -actin, were not altered by
troglitazone treatment. From these results, we postulate that chronic
troglitazone exposure may be creating a myotube that is able to
metabolize free fatty acids differently than the untreated type II
diabetic myotube.
Much of the work demonstrating that thiazolidinediones are ligands for
PPAR has been performed in adipocytes or adipocyte models, giving
rise to the hypothesis that adipose tissue is the major site of action
of these agents, and that any improvements in skeletal muscle insulin
action and glucose metabolism could be indirect because of lowering of
lipid levels and reduction of activity through the glucose-fatty acid
cycle (32). However, PPAR is also present in skeletal muscle (6, 7, 8, 12, 13), and the current results suggest that the thiazolidinediones
may also have direct effects in concert with the skeletal muscle
PPAR receptors.
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Acknowledgments |
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Footnotes |
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2 Supported by the Paul Dudley White Fellowship, American Heart
Association.
Received March 3, 1998.
Revised April 20, 1998.
Accepted May 7, 1998.
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