muscle fibre composition and glycogen synthase activity in hypertension-prone men

Journal of Internal Medicine 1998; 243: 141–147

© 1998 Blackwell Science Ltd 141

Muscle fibre composition and glycogen synthase activity inhypertension-prone men

T. ENDRE a , I . MATTIASSON a , G. BERGLUND a & U. L . HULTHÉN b

From the aDepartment of Medicine and bDepartment of Endocrinology, Malmö University Hospital, Lund University, Malmö; Sweden

Abstract. Endre T, Mattiasson I, Berglund G, HulthénUL (Malmö University Hospital, Lund University,Malmö; Sweden). Muscle fibre composition andglycogen synthase activity in hypertension-pronemen. J Intern Med 1998; 243: 141–147.

Objectives. To study muscle fibre characteristics andglycogen synthase activity in relation to peripheralglucose disposal in skeletal muscle in hypertension-prone men.Design. The hyperinsuliemic euglycemic clampmethod was used to calculate insulin sensitivityindex (M/I). Muscle biopsies were performed for theanalysis of slow-twitch (ST) and fast twitch (FT, lowinsulin sensitivity and low capillarisation comparedto ST fibres) muscle fibres, capillarisation (number ofcapillaries per fibre) and diffusional index (mean areaper fibre divided by capillarisation) of muscle fibres,capillary density (capillaries mm22 muscle fibre) andglycogen synthase activity.Subjects. Thirty-two young, healthy, normotensive

men with a family history of hypertension (REL)were compared to 25 age-matched men with no fam-ily history of hypertension (CON) and similar bodymass index (BMI).Results. REL had a lower M/I (P 5 0.021), lower capillarisation (P 5 0.04) and a tendency of a lower diffusional index of subgroup b of FT muscle fibres (P 5 0.10) compared to CON. Glycogensynthase activity did not differ between the groups.Conclusions. Men with a family history of hyperten-sion have less capillaries per FTb fibre and greater dif-fusion distance from the capillary to the muscle cellcompared to controls, which may be a contributoryfactor to the lower insulin sensitivity in the formergroup. However, additional investigations are neededto study the casuality in this association.

Keywords: euglycemic clamp technique, family histo-ry of hypertension, glycogen synthase, insulin resis-tance, muscle fibre type.

Introduction

Essential hypertension is associated with insulinresistance and hyperinsulinemia [1,2], and recentstudies have demonstrated that normotensive off-spring with a family history of hypertension havedecreased insulin sensitivity [3–5] which mayindicate an important role for insulin resistance inthe process of developing hypertension. Recentstudies have explored possible mechanisms forinsulin resistance. Insulin resistance have beenshown to be due to a decreased glucose uptake inskeletal muscle [6]. We recently showed that insulinresistance is coupled to low physical fitness innormotensive hypertension-prone men [5]. It hasbeen proposed that decreased insulin sensitivity may

be due to decreased skeletal muscle blood flow and/orgreater proportion of insulin resistant, poorly capil-larized and glycolytic fast-twitch skeletal musclefibres (type IIb) [7–9]. Hypertensive individuals havebeen shown to have more type IIb muscle fibres with low capillarisation that normotensive subjects[10, 11], and it has also been suggested thathypertensives have a defect non-oxidative glucosemetabolism with a reduced glycogen synthesis [12].Individuals at increased risk of developing non-insulin dependent diabetes mellitus (NIDDM), char-acterized by low pheripheral insulin sensitivity, havean impaired activation of the enzyme glycogensynthase [13].

To further elucidate the impact of muscle fibrecomposition and glycogen synthase activity on

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© 1998 Blackwell Science Ltd Journal of Internal Medicine 243: 141–147

insulin sensitivity, muscle biopsies were performedafter a euglycaemic hyperinsulinaemic clamp in nor-motensive men with a family history of hypertension(REL) and normotensive men with no family historyof hypertension (CON).

Methods

Subjects

Two groups of healthy young volunteers were inves-tigated, most of whom had participated in a studyperformed approximately two years earlier [5].Briefly, one group (REL) included sons of familieswith a documented family history of essential hyper-tension in either both parents, in one parent and onegrand-parent on the same side, or in one parent andone sibling. The other group included sons of familieswith no family history of hypertension (CON). To beincluded in the first study [5] the subjects were tohave a supine diastolic blood pressure consistentlybelow 90 mmHg, a normal glucose tolerance test and a gamma glutamyl transpeptidase (GT) below0.8 mkatL21 to exclude individuals with a high alco-hol consumption. CON were initially BMI-matchedconsecutively from screening lists, but due to drop-outs, it was no longer possible to BMI-match individ-uals. In the present study all participants from thefirst study were asked to participate. Among the REL35 subjects agreed to participate. In order to achievea greater number of control subjects due to drop-outs, four CON not participating in the first studywere included according to the inclusion criteriagiven above [5], giving a total of 27 CON. All partici-pants performed a euglycaemic hyperinsulinaemicclamp and an evaluation of physical fitness by esti-mating maximal oxygen uptake with a bicycleergometer test (see below). Muscle biopsies were suc-cessfully performed in 32 REL and 25 CON.

Study design

Before the investigation all subjects were to maintaintheir ordinary lifestyle and avoid excessive foodintake, alcohol consumption, and exercise. The sub-jects did not smoke or exercise and fasted overnightbefore the study.

Anthropometric measurements. In the morning ofthe study day the following anthropometric measure-

ments were performed. Body mass was measured tothe nearest 0.1 kg (with underwear), height to thenearest cm and BMI was calculated. Circumferencesof the waist and hip regions were measured at thelevels of the umbilicus and iliac crest respectively,giving the waist/hip ratio (WHR). Lean body mass(LBM) was determined by bioelectrical impedanceanalysis [14]. After 15 and 25 min of rest in a supineposition blood pressure was measured with a digitalblood pressure monitor (Omron Tateisi ElectronicsCo., Tokyo, Japan) using an oscillometric method.Blood samples for serum insulin, triglycerides andcholesterol were taken from an antecubital vein.

Euglycaemic hyperinsulinaemic clamp and muscle biopsy.A euglycaemic hyperinsulinaemic clamp [15] wasperformed to determine insulin sensitivity. Insulinand glucose were infused through a catheter inserted into an antecubital vein for 2 h. Arterialized blood samples for insulin and glucose were collectedfrom a contralateral antecubital vein after heating ofthe forearm. The steady-state serum insulin concen-tration was ,100 mU21 and the target level ofplasma glucose was 5.0 mmol21. The total amount ofglucose infused during the last hour is a measure ofinsulin sensitivity and was expressed relative to theprevailing insulin concentration. The glucosedisposal (M) was calculated as the amount ofglucose infused and is expressed per kg body weight(mg 3 kg b.w21 3 min21), and the insulin sensitivityindex is calculated as the amount of glucose metabo-lized per unit of plasma insulin multiplied by 100(M/I, where I 5 mean insulin concentrations at 60and 120 min). The reproducibility of the glucoseclamp method was investigated by comparing theinsulin sensitivity values from the first study [5] withthe values from the present study. Altogether 56subjects participated in both studies and the cor-relation between the two occasions was r 5 0.71 (P , 0.001) and the mean values were virtually thesame (8.1 (3.2) vs. 8.4 (3.9), P 5 0.56).

After 2 h, during insulin and glucose infusion, abiopsy of the lateral part of the quadriceps femorismuscle was performed [16].

Physical fitness evaluation. A few days after theinsulin sensitivity test a submaximal exercise testwas performed on a bicycle ergometer using a work-load of 100–225 W, depending on weight and self-reported physical activity, which lasted for 6 min

MUSCLE FIBRE CHARACTERISTICS AND HYPERTENSION 143


with continuous monitoring of heart rate. Meanheart rate during the last 2 min of work (steady-stateof $120 beats/min) was used for calculation of max-imal oxygen uptake (VO2max) according to a referencetable as described by Åstrand [17]. A comparisonbetween this indirect measure of VO2max and directmeasurement of VO2max made in 15 middle-aged, nor-motensive, mormoglycemic men and 13 normoten-sive men with impaired glucose tolerance in ourhospital showed the same mean values and coeffi-cients of variation less than 10% [18, 19]. A ques-tionnaire was used to classify self-estimated dailyphysical activity (SEPA) during work and leisure timeinto four (1–4) categories each [18]. Briefly, officework with no or very little physical demands wasclassified as category 1 and jobs with heavy manuallabour as category 4. Similarly, no physical activityduring leisure time was classified as category 1, andweekly bouts of endurance physical training wasclassified as category 4. A total score was given forwork 1 leisure time activity ranging from 2 to 8(SEPA-score).

Informed consent was obtained from each individ-ual and the study protocol was approved by theEthics Committee of the Faculty of Medicine,University of Lund.

Analytical procedures

Serum insulin was analysed with a RIA technique(precision: 5.5% at 18 mU and 7.1% at 157 mU) andblood lipids (serum triglycerides, total cholesterol,LDL-cholesterol and HDL-cholesterol) were analysedaccording to standard techniques at the Departmentof Clinical Chemistry at Malmö University Hospital.All samples were analyzed in the same assay with anintra-assay variation of ,7%. The muscle tissuesample was divided into two pieces, one for the analy-ses of glycogen synthase activity (GSA), and theother for histochemical analysis.

Glycogen synthase activity. One piece of muscle tis-sue was instantly frozen in liquid nitrogen. Thefrozen sample was homogenized in buffer containing50 mmol L21 morpholinopropane sulfonic acid(MOPS), 25 mmol L21 sodiumfluoride (NaF) and 25mmol L21 ethylenedinitriolo tetraacetic acid (EDTA),and thereafter incubated at 37 8C for 1.5 min with ahigh concentration (6 mmol L21) of glucose-6-phos-phate (g-6-p) or 5 min with a low g-6-p concentra-

tion (0.3 mmol L21). Glycogen synthase activity wasanalyzed on the basis of incorporation of 14C-labelled glucose (uridine diphosphate glucose [UDPG-14C], final concentration <0.04 mmol L21) intoglycogen with collection and measurement oflabelled glycogen [20]. The homogenate solution wasapplicated on a filter paper which stopped the reac-tion, and then washed with alcohol to eliminate non-bound 14C. The filter paper was dried for 1–2 hbefore measurement of 14C in a scintillation spec-trometer (Packard liquid scintillation spectrometer3330). The fractional velocity of glycogen synthaseactivity (FV, %) is the ratio of the value measuredwith the low g-6-p concentration and the value mea-sured with the high g-6-p concentration and repre-sents the fraction of the glycogen synthase activitywhich is influenced by insulin [13].

Muscle fibre histochemistry analysis. The other pieceof muscle tissue was embedded in plastic material(tissue-Tec) and frozen in isopentane cooled withliquid nitrogen. The samples were stored at 280 8Cbefore analysis. The frozen samples were cut at 220 8C in serial sections and stained for capillaries[21] and myofibrillar ATPase after preincubations atpH 4.3, 4.6 and 10.3 respectively, to estimate theproportion of slow twitch (ST, high capillary densityand highly-oxidative capacity) and fast twitch musclefibres of subgroups FTa (oxidative and glycolyticcapacity), and FTb (mainly glycolytic capacity, lowcapillary density) [22, 23]. The presented diffusionalindex of muscle fibres is calculated by dividing themean area per fibre by the number of capillaries perfibre [24]. Although there are no CV values for themuscle fibre analysis in the present study repeatedbiopsies from the vastus lateralis muscle have showna methodological error for estimating the ST fibretype of approximately 12% (coefficient of variation)[25].

Histochemical analysis of the muscle tissue sam-ples could not be performed in 13 REL and 5 CONdue to technical errors or insufficient amount ofmuscle tissue from the biopsy.

Statistical analyses

Values are presented as medians and quartiles(Q1:Q3) and the level of significance was taken asP , 0.05.

The non-parametric Mann–Whitney U-test was

T. ENDRE et al.144


used to test for significance of difference for unpaireddata.

Results

Basal characteristics and glucose metabolism

The two groups did not differ with respect to age andanthropometric measurements (Table 1). Systolicand diastolic blood pressure (SBP and DBP) werehigher in the REL compared to CON. Serumtriglycerides, total cholesterol and LDL-cholesterolwere also higher in REL than in CON but HDL-cholesterol did not differ between the groups(not shown).

Although self-estimated physical activity score wassimilar in the two groups, maximal oxygen uptakewas lower in REL compared with CON.

Fasting serum insulin was similar, but M/I weresignificantly lower in the REL versus CON.

Glycogen synthase activity

The two groups did not differ in GSA or FV (Table 2),which also applied to the individuals with successful-ly analyzed muscle fibre samples (CON vs REL,P 5 0.40 and P 5 0.45, respectively).

Muscle fibre characteristics

There was no significant difference between REL andCON with respect to the distribution (Area, %) of thedifferent muscle fibre types (Table 2). In REL the cap-illarisation was lower for FTb fibres. There were nosignificant differences in the capillary density or theratio of the area ST/FT, although capillary densitytended to be lower and diffusional index tended to behigher in REL. In individuals in whom muscle fibreanalysis was performed the M/I values were 9.0(6.1–11.6) in CON vs. 7.2 (4.6–8.3) in REL(P 5 0.13).

Muscle fibre characteristics in relation to W/H ratio

In an earlier study [5] we found that REL with a W/Hratio below the median value in CON (0.92) weremuch more insulin resistant and had a very low oxy-gen uptake as compared to corresponding CON. Thisfinding generated the hypothesis that the lowerinsulin sensitivity might be due to a difference inmuscle fibre composition between the groups.

The individuals participating in the first sub-grouping of subjects [5] performing in the presentstudy were 12 REL and 10 CON with a low W/H ratio(# 0.92) (Table 3).

REL with low W/H had lower maximal oxygenuptake and marginally lower M/I compared to CON,

Table 1 Basal characteristics, androgens and glucose metabolism in men without (CON) and with (REL) a family history of hypertension

CON RELVariable (n 5 25) (n 5 32) P

Age (years) 038 (32–43) 040 (33–43) 0.69

Body mass index (kgm22) 024.2 (23.0–25.6) 025.5 (23.7–27.2) 0.058

Lean body mass (kg) 063.8 (61.0–67.4) 064.8 (61.1–69.0) 0.48

Waist/hip ratio 000.96 (0.94–1.0) 000.98 (0.95–0.99) 0.47

Systolic blood pressure (mmHg) 122 (115–127) 131 (125–138) 0.001

Diastolic blood pressure (mmHg) 074 (68–82) 083 (78–87) 0.002

Heart rate (beats/minute) 060 (54–64) 064 (56–70) 0.10

Self-estimated physical activity score (2–8) 004 (4–6) 004 (3–5) 0.46

Maximal oxygen uptake (mL O2/kg b.w./min) 046 (37–59) 036 (30–44) 0.046

fSerum Insulin (mUL21) 007.0 (4.8–10.1) 009.5 (5.0–12.5) 0.18

Glucose disposal rate (M) (mgkg bw21min21) 009.5 (6.3–11.4) 007.2 (5.0–9.2) 0.069

Insulin sensitivity index (M/I) 008.4 (5.6–11.2) 005.2 (4.0–8.3) 0.015

Values are presented as medians and quartiles (Q1 and Q3).



and they had a lower percentage ST muscle fibres.The capillarization per ST muscle fibre was also mar-ginally lower, however the diffusional indices for allmuscle types did not differ.

Discussion

To explain the pathogenic mechanisms for reducedinsulin sensitivity in relation to oxygen uptake in off-spring of hypertensive parents, we performed a eug-lycemic hyperinsulinemic clamp in combination withmuscle biopsies. It was confirmed that REL had alower insulin sensitivity index and lower maximaloxygen uptake. The strong association between thesetwo parameters has been demonstrated before [5,26].

In the present study it was demonstrated that RELhave a significantly lower number of capillariesaround FTb muscle fibres. For the other fibre typesthere was a tendency towards lower capillarizationand a greater diffusional index in REL. The percent-age of slow-twitch muscle fibres in REL was also mar-ginally lower. In prediabetic individuals there is anincreased muscle capillary density compared to con-

trols [27]. Earlier studies have suggested that the dif-fusion distance from capillary to muscle cell and thecapillary density are possible determinants of in vivoinsulin sensitivity in man (24, 28]. Julius et al. haveproposed that the link between insulin sensitivity andhypertension is capillary rarefaction and type II mus-cle fibre predominance [8]. Hypertensive individualshave been shown to have a lower number of insulinsensitive, highly capillarized slow-twitch musclefibres compared to controls [10, 11]. Hence, theresults from the present study may indicate that ahigh diffusional index, low capillarization, and alower number of slow-twitch muscle fibres are possi-ble determinants for lower insulin sensitivity andmaximal oxygen uptake in REL [5]. Muscle fibre com-position is mainly determined genetically and is notinfluenced by physical activities [29]. Muscle fibrecapillarization, however, is highly influenced by levelof physical activity [30, 31]. In this study the level ofphysical activity did not differ between the groups;nevertheless maximal oxygen uptake was lower inthe REL. One hypothetical explanation for this maybe a genetically determined low number of slow-twitch muscle fibres with a decreased capacity to

Table 2 Glycogen synthase activity (GSA), fractional velocity (FV) of GSA and muscle fibre characteristics in men without (CON) and with(REL) a family history of hypertension


GSA (mmol min21gram21) 0000.77 (0.64–0.92) 0000.86 (0.66–1.06) 0.36Fractional velocity (%) 0006.7 (5.2–8.7) 0006.0 (4.6–9.3) 0.39

(n 5 20) (n 5 19)Area (%)-ST 0049.2 (40.6–60.0) 0042.9 (34.1–50.1) 0.12Area (%)-FT-total 0050.5 (40.6–59.0) 0057.2 (49.9–66.0) 0.10Area (%)-FTa 0040.3 (27.8–44.0) 0041.6 (34.7–50.4) 0.28Area (%)-FTb 0009.2 (5.4–14.2) 0014.2 (5.4–18.6) 0.48

Capillaries/ST 0003.3 (2.7–3.8) 0002.8 (1.6–3.6) 0.15Capillaries/FTa 0003.1 (2.7–3.5) 0002.6 (1.4–3.2) 0.13Capillaries/FTb 0002.6 (2.2–3.0) 0002.1 (1.1–2.5) 0.04

Diff. index (mm2)-ST 1092 (966–1408) 1320 (1179–2101) 0.09-FTa 1349 (1177–1537) 1639 (1257–2514) 0.15-FTb 1301 (1129–1710) 1751 (1316–2537) 0.10

Capillaries22mm 0318 (270–353) 0273 (176–323) 0.09

Area ST/FT 0000.98 (0.68–1.51) 0000.75 (0.52–1.01) 0.12

ST, FTa and Ftb denotes slow-twitch, fast-twitch (type a and b) muscle fibres, respectively. Diff. index denotes diffusional index (mean area perfibre capillary per fibre.Values are presented as medians and quartiles (Q1 and Q3).

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extract oxygen resulting in a lower physical capacity.The finding in the subgroup of REL with low W/Hratio of marginally lower insulin sensitivity index, alower oxygen uptake as well as a lower percentage ofST muscle fibres may support this hypothesis.

In the present study individuals at increased risk ofdeveloping hypertension had a similar glycogen syn-thase activity during euglycemic clamp as CONdespite decreased insulin sensitivity. Muscle glycogensynthesis is the principal pathway of glucose disposaland insulin resistance in patients with NIDDM ismainly due to reduced glycogen synthesis [32].Individuals at increased risk of developing NIDDMhave a defect activation of glycogen synthase duringa euglycemic hyperinsulinaemic clamp [13]. Patientswith primary hypertension have been shown to havea defect in non-oxidative glucose disposal [6]. Thisdefect cannot be overcome by exercise [33].

From these data it seems as if the mechanism forinsulin resistance in individuals with a family historyof hypertension is more likely a reduced capillarydensity than an intracellular defect as reduced activi-ty of glycogen synthase.

In conclusion, REL, have less capillaries per FTbfibre and marginally greater diffusion distance fromthe capillary to the muscle cell compared to CON,

and this may be a contributory factor to low insulinsensitivity in the former group. There was nodifference in glycogen synthase activity between thegroups so this cannot explain the lower glucosedisposal rate in REL in this study.

Acknowledgements

We are grateful to Professor Leif Groop and EsaLaurila for methodological discussions and adviceand to Gertrud Ahlqvist and Marianne Lundberg fortechnical assistance.

This study was supported by grants from theSwedish Heart and Lung Foundation, the NordicInsulin Fund, the Ernhold Lundströms ResearchFoundation, the Swedish Hoechst Diabetes Fund, theAlbert Påhlsson Research Foundation, MalmöDiabetes Association, the Research Funds of MalmöUniversity Hospital, Trygg-Hansa Research Fund,and the Medical Faculty, Lund University.

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Table 3 Characteristics of individuals below the 50th percentile of waist/hip ratio (#0.92) in men without (CON) and with (REL) a familyhistory of hypertension


Age (years) 0032 (29–40) 0040 (33–42)

Body mass index 0023.2 (22.5–25.4) 0024.8 (23.8–26.8)

W/H-ratio 0000.88 (0.81–0.92) 0000.86 (0.84–0.88)

Self-estimated physical activity score (2–8) 0005.0 (4.0–6.5) 0004.0 (3.0–5.0) 0.075

Maximal oxygen uptake (mL O2kg b.w.21min21) 0064 (42–69) 0038 (31–45) 0.009

Area (%)-ST 0051.0 (45.6–64.2) 0042.2 (29.1–46.9) 0.02Area (%)-FTa 0038.4 (30.7–45.3) 0042.8 (35.7–53.8) 0.17Area (%)-FTb 0007.2 (3.3–10.4) 0013.0 (6.8–18.0) 0.16

Capillaries/ST 0003.4 (2.7–3.8) 0002.7 (1.6–3.3) 0.14Capillaries/FTa 0003.0 (2.7–3.1) 0002.6 (1.4–3.3) 0.36Capillaries/FTb 0002.6 (2.2–3.0) 0002.0 (1.1–2.4) 0.074

Diff. Index-ST 1030 (938–1419) 1349 (1209–2073) 0.17Diff. Index-FTa 1359 (1177–1514) 1532 (1276–2625) 0.21Diff. Index-FTb 1202 (1104–1613) 1610 (1380–2549) 0.14

Insulin sensitivity index (M/I) 0010.0 (6.5–15.7) 0007.6 (5.1–8.3) 0.065

ST, FTa and FTb denotes slow-twitch, fast-twitch (type a and b) muscle fibres, respectively. M/I is glucose disposal rate (mgkg b.w.21min21)divided by the prevailing insulin concentration during glucose clamp. Values are presented as medians and quartiles (Q1 and Q3).



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Received 10 December 1996; accepted 21 August 1997.

Correspondence: Dr Tomas Endre, Department of Medicine,University Hospital MAS, S-20502 Malmö, Sweden (fax: 14640336208).

muscle fibre composition and glycogen synthase activity in hypertension-prone men

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