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Am J Physiol Endocrinol Metab 287: E305-E309, 2004. First published March 30, 2004; doi:10.1152/ajpendo.00082.2004
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Phorbol esters affect skeletal muscle glucose transport in a fiber type-specific manner

David C. Wright, Paige C. Geiger, Mark J. Rheinheimer, Dong Ho Han, and John O. Holloszy

Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Submitted 20 February 2004 ; accepted in final form 12 March 2004


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Recent evidence has shown that activation of lipid-sensitive protein kinase C (PKC) isoforms leads to skeletal muscle insulin resistance. However, earlier studies demonstrated that phorbol esters increase glucose transport in skeletal muscle. The purpose of the present study was to try to resolve this discrepancy. Treatment with the phorbol ester 12-deoxyphorbol-13-phenylacetate 20-acetate (dPPA) led to an ~3.5-fold increase in glucose transport in isolated fast-twitch epitrochlearis and flexor digitorum brevis muscles. Phorbol ester treatment was additive to a maximally effective concentration of insulin in fast-twitch skeletal muscles. Treatment with dPPA did not affect insulin signaling in the epitrochlearis. In contrast, phorbol esters had no effect on basal glucose transport and inhibited maximally insulin-stimulated glucose transport ~50% in isolated slow-twitch soleus muscle. Furthermore, dPPA treatment inhibited the insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and the threonine and serine phosphorylation of PKB by ~50% in the soleus. dPPA treatment also caused serine phosphorylation of IRS-1 in the slow-twitch soleus muscle. In conclusion, our results show that phorbol esters stimulate glucose transport in fast-twitch skeletal muscles and inhibit insulin signaling in slow-twitch soleus muscle of rats. These findings suggest that mechanisms other than PKC activation mediate lipotoxicity-induced whole body insulin resistance.

insulin resistance; insulin receptor substrate-1 phosphorylation; protein kinase C activation

SKELETAL MUSCLE INSULIN RESISTANCE is a component of the metabolic syndrome associated with abdominal/visceral obesity. It has been hypothesized that skeletal muscle insulin resistance is mediated by accumulation of intramuscular lipids, such as diacylglycerol and long-chain fatty acyl-CoAs, resulting in activation of conventional (c) and/or novel (n) protein kinase C (PKC) isoforms (12, 18, 23). In support of this hypothesis, it has been shown that elevation of plasma free fatty acids results in activation of PKCs with inhibition of insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation (23), phosphatidylinositol (PI) 3-kinase activation (23), and protein kinase B (PKB) phosphorylation (15). Further evidence includes the findings that PKC inhibitors reverse insulin resistance in muscle strips from obese patients (4) and that activation of PKCs with phorbol esters inhibits insulin signaling and glucose transport in isolated muscle preparations (4, 15). Although this evidence appears clear cut and convincing, its interpretation is confused by the diametrically opposed finding from our laboratory that activation of PKCs by phorbol esters results in stimulation of glucose transport in skeletal muscle (7, 11) that is additive to the maximal effect of insulin (7). The purpose of the present study was to test the hypothesis that this discrepancy is explained by differences in the response of glucose transport to activation of PKCs in slow-twitch and fast-twitch muscles.


   MATERIALS AND METHODS
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Materials. 2-Deoxy-[1,2-3H]glucose was purchased from American Radiolabeled Chemicals (St. Louis, MO). [14C]mannitol was obtained from ICN Radiochemicals (Irvine, CA). 12-Deoxyphorbol-13-phenylacetate 20-acetate (dPPA) and phorbol 12-myristate, 13-acetate (PMA) were obtained from LC Laboratories (Woburn, MA). Calphostin C was purchased from Calbiochem (La Jolla, CA). The anti-phosphotyrosine-608 IRS-1 and anti-phospho serine-612 IRS-1 antibodies were purchased from Biosource International (Camarillo, CA). Anti-phospho PKB threonine-308 and serine-473 antibodies were a product of Upstate Biotechnology (Lake Placid, NY). The horseradish peroxidase (HRP)-conjugated donkey anti-rabbit IgG was purchased from Jackson ImmunoResearch Laboratories (West Grove, PA). Enhanced chemiluminescence (ECL) reagents were obtained from Amersham (Arlington Heights, IL). All other chemicals were obtained from Sigma (St. Louis, MO).

Treatment of rats and muscle preparations. Male Wistar rats (Charles River) weighing ~80–120 grams were provided with Purina Rat Chow and water ad libitum. Food was removed at 5:00 PM the evening before the experiment. Rats were anesthetized by an intraperitoneal injection of pentobarbital sodium (5 mg/100 g body wt) followed by the removal of the fast-twitch white epitrochlearis (15% type I, 20% type IIa, 65% type IIb; see Ref. 17), fast-twitch red flexor digitorum brevis (FDB, 7% type I, 92% type IIa, 1% type IIb; see Ref. 3), and slow-twitch soleus (84% type I, 16% type II; see Ref. 1). Soleus muscles were split longitudinally into strips before incubation to allow adequate diffusion of oxygen and substrates (10). All protocols were approved by the Animal Studies Committee of Washington University.

Muscle treatments. After dissection, muscles were allowed to recover for 60 min in flasks containing 2 ml Krebs-Henseleit bicarbonate buffer (KHB) with 8 mM glucose, 32 mM mannitol, and a gas phase of 95% O2-5% CO2. The flasks were placed in a shaking incubator maintained at 35°C. After recovery, muscles were incubated in the same medium in the presence or absence of phorbol esters (0.1 µg/ml dPPA or 1.0 µg/ml PMA) for 90 min. Phorbol esters were solubilized in DMSO. An equivalent volume of DMSO was added to incubation medium of the control muscles. When calphostin C (0.5 µg/ml) was used, muscles were incubated for 60 min in KHB with the inhibitor before and also during exposure to dPPA. When insulin was used, it was present for the last 30 min of the 90-min incubation. Calphostin C and phorbol esters are light sensitive. Flasks containing these compounds were therefore wrapped in foil.

Measurement of glucose transport activity. After the various treatments, the muscles were rinsed for 10 min at 29°C in 2 ml oxygenated KHB containing 40 mM mannitol and the continued presence of dPPA and/or insulin. After the rinse step, glucose transport activity was measured using the glucose analog 2-deoxyglucose (2-DG), as described previously (22). Briefly, muscles were incubated for 20 min at 29°C in flasks containing 2 ml KHB with 4 mM 2-[1,2-3H]deoxyglucose (1.5 µCi/ml) and 36 mM [14C]mannitol (0.2 µCi/ml), with a gas phase of 95% O2-5% CO2, in a shaking incubator. The same additions that were in the preincubation were also present during the determination of glucose transport. The muscles were then blotted, clamp-frozen, and processed for determination of intracellular 2-DG accumulation and extracellular space, as described previously (22).

Western blotting. Clamp-frozen epitrochlearis and soleus muscles were homogenized in a 10:1 volume-to-weight ratio of ice cold buffer containing: 50 mM Tris·HCl (pH 7.4), 1% Nonidet P-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM each of EDTA, phenylmethylsulfonyl fluoride, and NaF, 1 µg/ml each of aprotinin, leupeptin, and pepstatin, 0.1 mM bis-peroxovanadium, 1,10-phenanthrolene, 25 µM okadaic acid, and 2 mg/ml {beta}-glycerophosphate. Homogenized samples were centrifuged for 15 min at 1,250 g at 4°C. The protein concentration of the supernatant was determined by the method of Lowry et al. (16). Proteins were separated (75 µg for PKB or 150 µg for IRS-1) by SDS-PAGE (6.25% resolving gel for IRS-1, 10% resolving gel for PKB), and Western blot analysis was used for the determination of PKB and IRS-1 phosphorylation (21). Anti-phospho PKB threonine-308 and serine-473 antibodies were used at a dilution of 1:1,000, and anti-phospho IRS-1 tyrosine-608 and serine-612 antibodies were diluted 1:500. HRP-conjugated donkey anti-rabbit IgG secondary antibody was used at a dilution of 1:5,000. Bands were visualized by ECL and quantified using densitometry.

Statistical analysis. Data are presented as means ± SE. Comparisons between the means of multiple groups were made using a one-way ANOVA followed by a post hoc comparison using Fisher’s protected least significant differences method. Statistical significance was set at P < 0.05.


   RESULTS
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DISCUSSION
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Phorbol esters stimulate glucose transport in fast-twitch muscles. It was previously shown that 0.1 µg/ml dPPA activates PKCs in skeletal muscle, as evidenced by an ~10-fold increase in MARCKS (myristoylated alanine-rich protein kinase C substrate) protein phosphorylation (7). As shown in Fig. 1A, treatment with dPPA led to an ~3.5-fold increase in glucose transport in the epitrochlearis muscle. A similar increase in glucose transport in response to treatment with dPPA was seen in the flexor digitorum brevis (FDB) (Fig. 1B). PMA also stimulated glucose transport, but to a smaller extent (data not shown). The increases in glucose transport induced by these phorbol esters were additive to the effect of a maximal insulin stimulus (Fig. 1). These findings are in keeping with previous results from our laboratory showing that phorbol esters increase glucose transport in the epitrochlearis (7, 11).



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  		Fig. 1. Stimulation of glucose transport activity by 12-deoxyphorbol-13-phenylacetate 20-acetate (dPPA) and/or insulin in rat epitrochlearis (A), flexor digitorum brevis (B), and soleus (C) muscles. Values are means + SE for 5–17 muscles/group. *P < 0.01 vs. basal. #P < 0.05 vs. all other groups. 2-DG, 2-deoxyglucose.

 
Phorbol esters inhibit insulin-stimulated glucose transport in soleus muscle. In contrast to the findings in fast-twitch muscles, treatment with dPPA (Fig. 1C) or PMA (data not shown) had no effect on basal glucose transport. However, treatment with phorbol esters resulted in an ~50% inhibition in maximally insulin-stimulated glucose transport in slow-twitch rat muscle.

Calphostin C partially reverses the attenuation of glucose transport by dPPA in soleus muscle. Phorbol esters activate both cPKC and nPKC isoforms. It was previously shown that calphostin C, a PKC inhibitor, partially prevented the stimulation of glucose transport in the epitrochlearis muscle by dPPA (7). As shown in Fig. 2, pretreatment with calphostin C partially prevented the inhibition of insulin-stimulated glucose transport induced by dPPA in the soleus.



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  		Fig. 2. Calphostin C partially prevents the dPPA-induced reduction in insulin-stimulated glucose transport in the soleus. Values are means + SE for 9–12 muscles/group. *P < 0.01 vs. insulin. #P < 0.01 vs. insulin + dPPA.

 
Phorbol esters attenuate insulin signaling in a fiber type-specific manner. It has been shown that the activation of PKCs leads to an inhibition of the insulin signaling pathway in slow-twitch skeletal muscle (4, 15, 23). In light of the difference in response to phorbol esters between fast-twitch and slow-twitch muscles, we compared the effects of dPPA on insulin signaling in the epitrochlearis and soleus.

As shown in Fig. 3A, a maximal insulin stimulus caused an approximately fourfold increase in the tyrosine phosphorylation of IRS-1 in the soleus muscle. Phosphorylation of PKB on threonine-308 and serine-473 also increased approximately fivefold in response to insulin in the soleus (Fig. 4). Treatment with dPPA resulted in an ~50% inhibition in the insulin-induced tyrosine phosphorylation of IRS-1 and serine/threonine phosphorylation of PKB. The magnitude of this inhibitory effect is comparable to the effect of dPPA treatment on insulin-stimulated glucose transport in the soleus.



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  		Fig. 3. A: insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is decreased in soleus muscle. B: serine phosphorylation of IRS-1 is increased by dPPA in rat soleus muscle. Values are means + SE for 4–6 muscles/group. *P < 0.01 vs. basal. #P < 0.05 vs. insulin alone.

 


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  		Fig. 4. Insulin-induced threonine (A) and serine (B) phosphorylation of protein kinase B (PKB) is decreased by dPPA in rat soleus muscle. Values are means + SE for 5–6 muscles/group. *P < 0.01 vs. basal. #P < 0.05 vs. insulin alone.

 
To evaluate the mechanism underlying the inhibitory effect of phorbol esters, we measured serine phosphorylation of IRS-1 on serine-612. The phosphorylation of this serine residue, which is homologous to serine-616 in humans, is thought to be the mechanism by which activation of PKC attenuates insulin signaling (5). As shown in Fig. 3B, dPPA resulted in a significant increase in IRS-1 serine phosphorylation under basal and insulin-stimulated conditions in the soleus.

In contrast to the slow-twitch soleus, dPPA had no effect on insulin signaling in the fast-twitch epitrochlearis muscle, as evidenced by normal insulin-stimulated tyrosine phosphorylation of IRS-1 (Fig. 3A) and of threonine-308 and serine-473 phosphorylation of PKB (Fig. 4). Furthermore, dPPA did not increase serine phosphorylation of IRS-1 in the epitrochlearis (Fig. 3B).


   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Early studies by Farese's group led to the hypothesis that activation of cPKCs mediates the stimulation of glucose transport by insulin (19, 20). Although this hypothesis proved to be incorrect, we have shown that the activation of PKCs by phorbol esters does stimulate glucose transport in rat epitrochlearis muscles (7, 11). However, this effect is independent of insulin signaling and additive to the effect of a maximal insulin stimulus (7).

Recent studies have led to the opposite conclusion that, rather than stimulating glucose transport, activation of cPKCs and/or nPKCs leads to skeletal muscle insulin resistance. One line of evidence suggesting that activation of PKC causes muscle insulin resistance came from studies in which feeding a high-fat diet or acutely raising plasma free fatty acids resulted in the lipid-induced activation of PKCs (12, 18, 23). Further evidence came from studies of muscle from obese insulin-resistant humans (4, 13) in which membrane-associated PKC-{beta} was elevated under basal conditions and total membrane-associated PKC activity was greater in response to insulin stimulation in muscles of obese compared with lean individuals (13). Furthermore, treatment of muscle strips from insulin-resistant patients with a PKC inhibitor significantly increased insulin-stimulated glucose transport, whereas activation of PKC with dPPA caused insulin resistance of muscle from insulin-sensitive nonobese individuals (4). Similarly, treatment of rat soleus muscles with a phorbol ester was found to result in severe impairment of insulin signaling and insulin-stimulated glycogen synthesis (15).

The purpose of the present study was to try to resolve the major discrepancy between studies showing that activation of cPKCs and/or nPKCs stimulates glucose transport in skeletal muscle and those indicating that PKC activation causes insulin resistance of glucose transport. Our findings on the effects of dPPA on rat soleus muscle confirm previous reports that activation of PKCs causes severe insulin resistance in slow-twitch skeletal muscle, including soleus (15) and human rectus abdominus muscle (4, 13).

There is considerable evidence that induction of muscle insulin resistance by PKC activation is mediated by inhibition of insulin signaling. This is evidenced by reductions in IRS-1 tyrosine phosphorylation (5, 23), PI 3-kinase activation (23), and PKB phosphorylation (15). The inhibition of tyrosine phosphorylation of IRS-1 appears to be mediated by serine phosphorylation (5, 23). Our findings in the soleus showing that treatment with dPPA resulted in inhibition of IRS-1 tyrosine phosphorylation, presumably by phosphorylation of serine-612, and inhibition of PKB activation, as evidenced by decreases in serine/threonine phosphorylation, provide further evidence that activation of PKC can induce insulin resistance in slow-twitch skeletal muscle.

However, in contrast to the results obtained in soleus muscle, our findings in the fast-twitch white epitrochlearis and fast-twitch red FDB muscles clearly show that activation of cPKCs and/or nPKCs stimulates glucose transport in fast-twitch muscle. Furthermore, as in our previous study (7), the stimulatory effect of phorbol esters was additive to the maximal effect of insulin on glucose transport, and dPPA treatment had no inhibitory effect on insulin signaling. Thus there are two major differences between slow- and fast-twitch rat skeletal muscles in their responses to PKC activation. One is that activation of PKCs causes serine phosphorylation and inhibition of IRS-1 tyrosine phosphorylation in the soleus but not in the fast-twitch epitrochlearis. The other is that treatment with phorbol esters stimulates glucose transport in the fast-twitch epitrochlearis and FDB, but not in the soleus muscle. These remarkable differences are surprising and currently unexplained. However, they do, to a large extent, explain the discrepancy between previous studies showing that agents that activate c- or nPKCs stimulate glucose transport in muscle and those showing an inhibitory effect on insulin-stimulated glucose transport.

In light of these findings, the interpretation of previous studies that induction of whole body insulin resistance by elevations of plasma free fatty acids is mediated by activation of PKC in skeletal muscle needs to be reevaluated. In the rat, ~10% of the skeletal muscle fibers are slow-twitch red (2). Therefore, inhibition of glucose transport in 10% of the muscle fibers by a mechanism that stimulates glucose transport in 90% of muscle fibers seems an unlikely explanation for whole body insulin resistance induced by lipotoxicity. Furthermore, a high-fat diet causes marked insulin resistance of the fast-twitch rat epitrochlearis muscle (6, 8, 9, 14). On the other hand, slow-twitch muscle fibers usually account for ~50% or more of total muscle mass in humans and are more insulin responsive than fast-twitch fibers. Although this makes PKC activation a more plausible explanation for lipotoxicity-induced insulin resistance in humans than in rats, it seems somewhat unlikely that insulin resistance associated with lipotoxicity is mediated by different mechanisms in species that respond so similarly to elevations in plasma fatty acids.

In conclusion, our results show that phorbol esters stimulate glucose transport in fast-twitch skeletal muscles and inhibit insulin signaling in slow-twitch red skeletal muscle of rats. These findings help to explain the discrepancy between previous studies reporting that activation of PKC activates or inhibits glucose transport in muscle. They suggest the likelihood that some mechanism other than PKC activation mediates lipotoxicity-induced muscle insulin resistance.


   GRANTS
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 MATERIALS AND METHODS
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This research was supported by National Institutes of Health (NIH) Grant DK-18986. D. C. Wright was supported by an American Diabetes Association Mentor-Based Postdoctoral Fellowship. P. C. Geiger was supported by NIH Institutional National Research Service Award AG-00078.


   ACKNOWLEDGMENTS
 
We thank Kathleen Hucker for excellent technical assistance and Victoria Reckamp for expert assistance in preparation of this manuscript.


   FOOTNOTES
 

Address for correspondence: J. O. Holloszy, Washington Univ. School of Medicine, Section of Applied Physiology, Campus Box 8113, 4566 Scott Ave., St. Louis, MO 63110 (E-mail: jhollosz{at}im.wustl.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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