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. Author manuscript; available in PMC: 2022 Aug 9.
Published in final edited form as: Appl Physiol Nutr Metab. 2021 Mar 25;46(6):685–689. doi: 10.1139/apnm-2021-0130

Reduced Membrane Cholesterol Content in Skeletal Muscle Is Not Essential for Greater Insulin-stimulated Glucose Uptake after Acute Exercise by Rats

Haiyan Wang 1, Edward B Arias 1, Gregory D Cartee 1
PMCID: PMC9359348  NIHMSID: NIHMS1827060  PMID: 33765397

Abstract

One exercise session can elevate insulin-stimulated glucose uptake (GU) by skeletal muscle, but it is uncertain if this effect is accompanied by altered membrane cholesterol content, which is reportedly inversely related to insulin-stimulated GU. Muscles from sedentary (SED) or exercised 3hours post-exercise (3hPEX) rats were evaluated for: GU, membrane cholesterol, and phosphorylation of cholesterol regulatory proteins (pHMCGRSer872 and pABCA1Ser2054). Insulin-stimulated GU for 3hPEX exceeded SED. Membrane cholesterol, pHMCGRSer872 and pABCA1Ser2054 did not differ between groups.

Novelty

Alterations in membrane cholesterol and phosphorylation of proteins that regulate muscle cholesterol are not essential for elevated insulin-stimulated GU in skeletal muscle after acute exercise.

Keywords: glucose uptake, membrane cholesterol, exercise

Introduction

Skeletal muscle is the major site for insulin-stimulated glucose disposal (DeFronzo et al., 1981). One exercise session can increase insulin-stimulated glucose uptake (GU) in skeletal muscle for 2-48 h post-exercise (Cartee, 2015, Wojtaszewski et al., 2003, Funai et al., 2009). However, the mechanisms involved in this important exercise benefit remain incompletely understood.

An inverse relationship has been reported between membrane cholesterol content and insulin-stimulated GU in skeletal muscle. (Sanchez-Aguilera et al., 2018, Grice et al., 2019, Habegger et al., 2012b). A recent study observed that chronic exercise by insulin resistant mice normalized their elevated membrane cholesterol content concomitant with improved insulin-stimulated GU in skeletal muscle (Ambery et al., 2017). However, little is known about the acute exercise effect on muscle membrane cholesterol.

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis, is phosphorylated and inactivated by AMPK (Clarke and Hardie, 1990, Sato et al., 1993). Increased membrane cholesterol content is associated with activation of HMGCR in myocytes (Habegger et al., 2012b). Evidence suggests that ATP-binding cassette transporter A1 (ABCA1), which plays a major role in cellular cholesterol efflux (Larrede et al., 2009, Wang and Tall, 2003), may influence glucose tolerance and insulin sensitivity (Key et al., 2017, Sanchez-Aguilera et al., 2018, de Haan et al., 2014).

Our primary goal was to investigate if increased insulin-stimulated GU post-exercise was accompanied by lower membrane cholesterol in muscle from rats. We also assessed exercise effects on the phosphorylation of key cholesterol regulatory proteins (HMGCR and ABCA1) in skeletal muscle.

Materials and Methods

Materials

Chemicals were obtained from Sigma-Aldrich (St. Louis,MO) or Fisher Scientific (Hanover Park,IL) unless otherwise noted. Pierce MemCode Reversible Protein Stain Kit (#24585), Bicinchoninic acid protein assay (#23225), Tissue Protein Extraction Reagent (TPER; #78510) and Amplex™ Red Cholesterol Assay Kit (#A12216) were obtained from Thermo Fisher Scientific (Waltham,MA). Anti-phospho Akt Ser473 (pAktSer473; #9271), anti-phospho Akt Thr308 (pAktThr308; #13038), anti-Akt (#4691), anti-phospho AS160 Thr642 (pAS160Thr642; #8881), anti-phospho AMPKα Thr172 (pAMPKαThr172; #2531), anti-AMP-activated protein kinase-α (AMPKα; #5831), anti-ryanodine receptor 1 (RyR1; #8153), anti-insulin receptor (IR; #3025), anti-α-Tubulin (#2144) and anti-rabbit IgG horseradish peroxidase conjugate (#7074) were from Cell Signaling Technology (Danvers,MA). Anti-Akt Substrate of 160 kDa (AS160; #ABS54) was from EMD Millipore (Billerica,MA). Anti-HMG-CoA Reductase (HMGCR, #BS-5068R) and anti-phospho HMG-CoA Reductase Ser872 (pHMGCRSer872, #BS-4063R) were from Bioss Antibodies (Woburn,MA). Anti-ATP Binding Cassette Subfamily A Member 1 (ABCA1, #NB400-105SS) was from Novus Biologicals (Littleton,CO). Anti-phospho ABCA1 Ser2054 was from Abcam (Cambridge,MA). 2-Deoxy-D-[3H]-glucose ([3H]-2-DG) and [14C]-mannitol were from Perkin Elmer (Boston,MA).

Animals

Animal care procedures were approved by the University of Michigan Committee on Use and Care of Animals and performed based on the guidelines from the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, USA. Male Wistar rats (12-15 weeks-old) were housed on a 12:12 hour light:dark cycle (lights out at 1700) with access to water and chow.

Exercise

Food was removed from rats at ~17:00 the night before the experiment. The following morning (~08:30), rats were randomly assigned to sedentary or exercise (swimming in a barrel filled with water,35°C, for 4×30min bouts, with 5min rest between bouts) groups.

Muscle Incubation for Glucose Uptake

Rats were anesthetized (intraperitoneal ketamine/xylazine injection) at 3h post-exercise (3hPEX) along with sedentary rats. Both epitrochlearis muscles were dissected out and placed in vials that were gassed (95% O2, 5% CO2) in a temperature-controlled water bath (35°C). During step 1 (30minutes), muscles were incubated with Krebs Henseleit (KHB) supplemented with 0.1% bovine serum albumin (BSA), 2mM sodium pyruvate, 6mM mannitol ±insulin (0.6nM). During step 2 (20minutes), muscles were incubated with KHB/BSA, the same insulin concentration as step 1, 1mM 2-DG (2.25 mCi/mmol3H–2-DG), and 9 mM mannitol (0.022 mCi/mmol 14C-mannitol). After step 2, muscles were blotted, freeze-clamped, and stored (−80°C) until analyzed.

Muscle Lysate Preparation

Frozen muscles were weighed and homogenized as previously described (Arias et al., 2007).

2-Deoxy-D-glucose (2-DG) Uptake

2-DG uptake was calculated as previously described (Cartee and Bohn, 1995).

Membrane fractionation and cholesterol content

Membrane-enriched and cytosol-depleted fractions were obtained by differential centrifugation as previously described (Grice et al., 2019). Membrane enrichment was assessed by immunoblotting with antibodies against membrane marker proteins (insulin receptor, IR; Na+/K+-ATPase; ryanodine receptor 1, RYR1) and a cytosolic marker protein (α-tubulin). Cholesterol in the membrane-enriched fraction was determined using the Amplex Red Cholesterol Assay Kit (Thermo Scientific; #A12216) as previously described (Grice et al., 2019).

Immunoblotting

Immunblotting was performed as previously described (Arias et al., 2007). Samples from SED and 3hPEX groups were loaded in alternating lanes of the gels.

Statistical Analysis

Student’s t-test was used for comparison between two groups. Two-way analysis of variance (ANOVA) was used to identify main effects of insulin (basal or insulin) and exercise (SED or 3hPEX). Post-hoc analysis used the Tukey test.

Results

2-Deoxy-D-glucose Uptake

There were significant main effects of insulin (insulin>basal, P<0.01) and exercise (3hPEX>SED; P<0.01, Figure 1) for GU. Post-hoc analysis indicated insulin-stimulated muscles had greater GU than paired muscles incubated without insulin for both SED and 3hPEX groups (P<0.05). GU by insulin-stimulated muscles from the 3hPEX group exceeded SED-controls (P<0.01).

Figure 1.

Figure 1.

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2-DG uptake in paired muscles incubated±insulin (100μU/ml). *P<0.05 Insulin versus Basal in both SED and 3hPEX; †P<0.01, 3hPEX versus SED with insulin. Data were analyzed by two-way ANOVA, values are means±SD; n=5-6 per group.

Membrane Cholesterol Content

The membrane fraction was enriched with membrane markers (IR, Na+/K+-ATPase, and RYR1) and depleted for the cytosolic marker (α-tubulin, Figure 2A). Membrane cholesterol was unaltered after exercise (Figure 2B).

Figure 2.

Figure 2.

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A: Blots of membrane and cytosolic marker proteins, B: Membrane cholesterol content, n=9 per group. C: pHMGCRSer872/HMGCR and D: pABCA1Ser2054/ABCA1, in muscles, n=5-6 per group. Data were analyzed by Student’s t-test, values are means±SD.

Immunoblotting

HMGCR and ABCA1 Phosphorylation

pHMGCRSer872/HMGCR and pABCA1Ser2054/ABCA1 values did not differ between 3hPEX and SED groups (Figures 2C and 2D).

Akt and AS160 Phosphorylation

There was a significant main effect of insulin (insulin>basal, P<0.001, Figures 3A and 3B) for pAkt on Thr308 and Ser473. Post-hoc analysis indicated insulin-treated muscles exceeded paired muscles incubated without insulin for SED and 3hPEX groups (P<0.01 for pAktThr308/Akt; P<0.001 for pAktSer473/Akt).

Figure 3.

Figure 3.

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A: pAktThr308/Akt, B: pAktSer473/Akt, C: pAS160Thr642/AS160 in paired muscles incubated±insulin (100μU/ml). *Insulin versus Basal in both the SED and the 3hPEX groups (P<0.01 for pAktThr308/Akt, P<0.001 for pAktSer473/Akt, P<0.05 for pAS160Thr642/AS160). †P<0.01, 3hPEX versus SED with insulin. Data were analyzed by two-way ANOVA, Values are means ±SD; n=5-6 per group. D: pAMPKThr172/AMPK, in muscles. *P<0.05; 3hPEX versus SED. Data were analyzed by Student’s t-test, values are means±SD; n=5-6 per group.

For pAS160Thr642/AS160, there were significant main effects of insulin (insulin>basal, P< 0.001) and exercise (3hPEX>SED; P<0.01, Figure 3C). Post-hoc analysis indicated insulin-treated muscles had greater pAS160Thr642/AS160 than paired muscles incubated without insulin for both SED and 3hPEX groups (P<0.05). pAS160Thr642/AS160 was significantly greater (P<0.01) for 3hPEX compared with SED controls with insulin.

AMPKα Phosphorylation

The pAMPKαThr172/AMPKα values were significantly greater (P<0.05, Figure 3D) for the 3hPEX group versus SED controls.

Discussion

Previous studies reported an inverse relationship between membrane cholesterol and insulin-stimulated GU in muscle (Llanos et al., 2015, Habegger et al., 2012b). Insulin-stimulated GU was reportedly decreased in muscles from insulin-resistant mice by a mechanism related to membrane cholesterol content (Ambery et al., 2017, Grice et al., 2019). Impaired insulin-stimulated GU was found to be associated with increased membrane cholesterol content in rat L6 myotubes (Habegger et al., 2012a, Habegger et al., 2012b). Normalization of excess membrane cholesterol improved insulin-stimulated GU in myocytes and myofibers (Habegger et al., 2012b, Sanchez-Aguilera et al., 2018, Llanos et al., 2015). A recent study reported that 2 weeks of exercise training improved insulin-stimulated GU concomitant with reduced membrane cholesterol content in muscle from high-fat-fed, insulin-resistant mice (Ambery et al., 2017). These studies suggest that membrane cholesterol can regulate insulin-stimulated GU. However, earlier studies have not probed the effect of acute exercise on muscle membrane cholesterol. Consistent with earlier research (Arias et al., 2007, Wang et al., 2018, Schweitzer et al., 2012), greater insulin-stimulated GU was observed in the current study after one exercise session. The major novel finding was that this exercise-benefit on insulin-stimulated GU was not attributable to reduced membrane cholesterol.

HMGCR and ABCA1 are key cholesterol regulatory proteins. Earlier research indicated activation of HMGCR regulates membrane cholesterol in myocytes (Habegger et al., 2012b). Cholesterol was elevated and insulin-stimulated GU was reduced in the adipose tissue of ABCA1-deficient mice (de Haan et al., 2014). Insulin-resistant humans versus healthy humans were characterized by increased plasma cholesterol and downregulation of the ABC transporter pathway in muscle (Tonks et al., 2016). One study reported evidence that the expression of ABCA1 contributes to lowering cholesterol accumulation and improved GU of myofibers in the insulin-resistance condition (Sanchez-Aguilera et al., 2018). In this context, it is notable that the absence of an exercise effect on membrane cholesterol content in muscles in the current study was accompanied by unaltered phosphorylation of HMGCR or ABCA1. The current results for acute exercise in healthy rats do not eliminate the possibility that improved insulin sensitivity after acute or chronic exercise by insulin resistant animals or humans may involve mechanisms related to membrane cholesterol.

AMPK activation has been linked to enhanced insulin sensitivity (Fisher et al., 2002, Kjobsted et al., 2016), and AMPK can phosphorylate and thereby inhibit HMGCR (Sato et al., 1993, Clarke and Hardie, 1990). A previous study provided evidence that activating AMPK using 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside enhanced insulin sensitivity via lowering membrane cholesterol in rat L6 myotubes (Habegger et al., 2012a). In the current study, the effect of exercise pAMPKThr172 remained detectable at 3hPEX. However, pHMGCRSer872 and membrane cholesterol content did not differ between the 3hPEX and SED-controls, suggesting that the putative relationship between AMPK and insulin sensitivity post-exercise depends on other mechanisms.

Substantial evidence links Akt substrate of 160 kDa (AS160) to insulin-stimulated GU (Sano et al., 2003, Chen et al., 2011, Cartee, 2015). In the current study, greater AS160 phosphorylation on Thr642 was accompanied by improved insulin-stimulated GU, consistent with earlier research (Schweitzer et al., 2012, Wang et al., 2018, Castorena et al., 2014). These results indicate that altered membrane cholesterol content was unnecessary for elevated AS160 phosphorylation post-exercise.

The enhanced insulin-stimulated GU in this study was reminiscent of results after treadmill exercise by rodents, or after treadmill or cycling exercise by humans (Cartee, 2015). In rats performing the exercise protocol used in this study, we previously measured insulin-stimulated GU by the extensor digiti quinti proprius (EDQP), a forelimb muscle with a fiber-type composition similar to the epitrochlearis (Wang et al., 2018). Swim-exercise did not alter insulin-stimulated GU in the EDQP, arguing against the possibility that the exercise-effect in the epitrochlearis was a nonspecific stress response.

The current study revealed that acute exercise-induced reduction in membrane cholesterol content is not essential for elevated insulin-stimulated GU in muscle from healthy rats. Furthermore, the lack of decreased membrane cholesterol content post-exercise was consistent with the observation of unaltered phosphorylation of HMGCR Ser872 and ABCA1 Ser2054, proteins with important roles in regulating cholesterol.

Acknowledgement

This research was supported by grants from the National Institutes of Health (DK71771). We thank Dominic Thorley and Gengfu Dong for research assistance.

Footnotes

Disclosures

No conflicts of interest, financial or otherwise, are declared by the authors.

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