Muscle ubiquinone and plasma antioxidants in effort angina

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Twelve male patients with effort angina had needle muscle biopsies taken from their vastus lateralis the day before coronary bypass and during surgery from gastrocnemius muscles for fibre typing and muscle ubiquinone (vitamin Q) determinations. They also had blood samples saved for analyses of ubiquinone (UQ, blood and plasma), a-tocopherol (AT, vitamin E, plasma) and free cholesterol (FC, plasma). FC marks for the lipophilic compound deposition volume and is used to calculate standardized UQ and AT (SUQ and SAT). Vastus lateralis muscle had a decreased percentage distribution of slow twitch muscle fibers (39 + 4 (SEM) %ST) for the age group but a normal proportion of the fast twitch (FT) 'intermediate oxidative' subgroup Fta (35 + 5%Fta). Muscle UQ was normal, whereas SUQ and SAT were reduced in relation to healthy individuals. Muscle UQ, SUQ and SAT normalized for oxidative muscle fibre types decreased the higher the muscle oxidative fibre proportion. It was concluded that the antioxidative potential in plasma and muscle was interrelated. This reflects an increased reactive radical species formation related to oxygen metabolism and turnover and a subsequent toll on antioxidant capacity.

Keywords: effort angina, antioxidants, ubiquinone, vitamin Q, vitamin E, muscle fibre types, muscle oxidative capacity.

INTRODUCTION
We have earlier documented that effort angina patients had a reduced vastus lateralis muscle content of ubiquinone (UQ) and an increased proportion of the glycogenolytic, 'white', fast twitch (FT) muscle fibre type, especially of its trauma-indicative subgroup, Ftc fibers [ 1-3].

UQ serves two functions in all investigated cells and tissues: ( 1) as a coenzyme in the mitochondria (coenzyme Q( 10), CoQ( 10), linking the citric acid (tricarboxylic acid, TCA) cycle to the respiratory chain, and ( 2) as a lipophilic antioxidant [ 4-6].

An increased proportion of FT muscle fibers is in agreement with other studies in patients with cardiovascular diseases [ 7-9]. This main fibre type is surrounded by a less dense capillary network than the other main fibre type, the 'red', oxidative, slow twitch (ST) fibre [ 10]. Fewer capillaries result in an increased peripheral resistance [ 11, 12].

The presence of Ftc muscle fibers was suggested as being causally related to the lowered muscle content of UQ [ 1-3]. It was possible to show an inverse relationship between percentage distribution of the oxidative ST fibers (%ST) and muscle UQ compared with a healthy person [ 4]. In addition, different mitochondrial enzyme markers were changed, which further supported the notion of radical-induced biochemical lesions [ 2, 13].

We thought it would be of interest to extend comparisons in this patient category to the relationships between muscle UQ and the plasma antioxidants UQ (vitamin Q [ 14]) and a-tocopherol (vitamin E). Moreover, whether these plasma antioxidant vitamins are related to muscle quality and/or are markers of muscle oxygen metabolism, and the subsequent, expected radical formation and toll on muscle and plasma antioxidants is also important.

PATIENTS AND METHODS
Twelve male patients accepted for coronary surgery were recruited (see Table 1). They had no major disease other than their ischemic heart disease (IHD). Medical treatment consisted of -adrenergic blockade, combined in most cases with Ca-entry blockers and/or nitrates. The study was approved by the hospital's Ethical Committee and the patient's formal consent was required.

The day before surgery, an exercise stress test was performed according to OBLA protocol [ 15] to determine the work load eliciting a blood lactate concentration of 2.0 mmol l-( 1) (WOBLA) and the symptomlimited ('maximal') exercise capacity (WSL)[ 1].

Needle muscle biopsy specimens from the vastus lateralis muscle were secured on the same day and before the exercise stress test [ 16]. During surgery, open biopsies were also saved from the gastrocnemius muscle. The specimens were immediately frozen in isopen-tane chilled with liquid nitrogen and stored at -80 degrees C until further analyses.

Deep vein blood samples were drawn twice: ( 1) during the rest period preceding the muscle biopsy and ( 2) before surgery started the day after.

Conventional histological procedures were undertaken to identify the two main muscle fibre types: ST and FT [ 17, 18]. The FT fibre group was reanalyzed with respect to the subgroups Fta, Ftb and Ftc, where Fta and Ftc indicate transition states of the more genuine FT fibre Ftb [ 18]. The presence of Fta signals an endurance adaptation, including increased local oxidative activity, and Ftc signals inflammatory processes.

Analyses for skeletal muscle UQ (vitamin Q) content were performed on freeze-dried specimens [ 19]. Corresponding analyses were also performed on blood and plasma samples. For plasma, a-tocopherol (AT) and free cholesterol (FC) were also included in the analyses [ 20]. Plasma values are presented as actual plasma concentrations and recalculated for the mean plasma FC in healthy individuals, i.e. 0.60mg 1-( 1) [ 21] (standardized ubiquinone, SUQ, and standardized a-tocopherol, SAT).

Based on muscle fibre types and UQ analyses, the muscle quality index (MQI) [ 1] was computed as the ratio of muscle UQ to %ST (UQ x %ST-( 1). In the present study, MQI was also computed for the sum of the oxidative muscle fibers: %ST + %Fta = %(ST + Fta). In accordance with MQI, the corresponding computations for plasma antioxidants were also undertaken: SUQ:%SAT and SAT:%ST (SUQ x %ST-( 1) and SAT X %ST-( 1)).

Some muscle histochemical and exercise performance data have been presented elsewhere [ 22, 23].

Conventional parametric statistics were applied to calculate means, standard error of the mean ( + 1 SEM), standard deviation (SD) and best fit curves. Regression was evaluated assuming a linear relationship. Differences between means were evaluated with Student's t-test for unpaired observations.

RESULTS
Pertinent anthropometric, exercise capacity and muscle histochemical data for these patients are presented in Tables 1 and 2.

Blood and Plasma Antioxidants
Mean plasma UQ values in the double determinations were almost identical: 0.83 and 0.88 mg 1-( 1) (0.96 and 1.02 #tool 1-1) (Table 3) (r = 0.94, p < 0.001, r( 2)=0.87). Plasma AT and FC, averaged in the first set of plasma samples, were 12.1 mg 1-( 1) (28.1 umol 1-( 1)) and 0.75 g 1-1 (1.94 mmol 1( 1)) (Table 3). Close identities were also present for these double determinations (AT: r = 0.97, p < 0.001, r( 2) = 0.85; FC: r = 0.79, p < 0.001, r( 2) = 0.59).

Although large individual variations were present, mean blood and plasma UQ levels were almost identical (Table 3) (r = 0.93, p < 0.001, r( 2) = 0.87; r = 0.96, p < 0.001, r( 2) = 0.91), i.e. all UQ was allocated to the plasma fraction.

Both plasma UQ and AT were related to the plasma lipid marker FC (r = 0.65, p < 0.01; r = 0.90, p < 0.001). As a consequence, plasma UQ and AT were interrelated (r = 0.68, p < 0.05), as was previously reported for healthy individuals [ 20].

Plasma FC also decreased with (BMI) and body weight (Fig. 1 (a)). Plasma UQ and also SUQ decreased with body weight (Fig. l(b)) or BMI (for both plasma UQ and SUQ: r = 0.58, p < 0.05). Plasma AT and SAT did not vary with either BMI or body weight. SUQ and SAT were lower than in healthy people (Fig. 2(a) and (b)).

Muscle UQ and Plasma Antioxidants
Percentage distribution of ST fibers (%ST) in the present patients (39%, Table 2) was lower than in age-matched sedentary males (55 +4%, p <0.001 [ 24, 25]). Percentage Fta (%Fta), on the other hand, was identical (34 + 4%). UQ content in the vastus lateralis and gastrocnemius muscles averaged 0.22 + 0.02 and 0.20 + 0.04 mg g-( 1) (260 and 232 #mol kg-( 1)), which was no different to healthy individuals [ 4]. No relationship was present between muscle UQ and plasma UQ or AT. Introduction of SUQ or SAT in the computations did not change this result.

The effort angina patients had a negative relationship between muscle quality index (MQI) and %(ST+Fta) (Fig. 3(a)). MQI in the vastus lateralis muscle averaged 6.47x 10-3 units as compared with 4.26-+0.26 (multiply) 03 units in healthy people (p < 0.01) [ 4]. This difference was explained by the lower %ST in the patients. Both groups were found to follow the same function between MQI and %ST (Fig. 3(b)).

MQI in the gastrocnemius was lower than in the vastus lateralis muscle (p < 0.001) (Table 2). When the gastrocnemius MQI was compared with the corresponding %ST value, it was concluded that the gastrocnemius muscle also followed the same function as for healthy individuals (Fig. 3(b)).

In accordance with the impact of muscle fibre composition on MQI is the fact that MQI computations based on %(ST + Fta) were similar for the vastus and gastrocnemius muscles (Table 2). A line of identity analysis of individual MQIs for the two muscles further emphasized this point (Fig. 3(c)).

The ratios of SUQ and SAT to the muscle distribution of oxidative fibers showed that the SUQ ratio decreases versus muscle fibre distribution expressed as either %ST or %(ST + Fta) (Fig. 4(a)), but this is only true for the SAT ratio to %ST (r = -0.73, p <0.`). It was obvious that the SUQ to percentage oxidative muscle fibers ratio represented a negative curvilinear relationship (Fig. 4(a)). If all the points in Fig. 4(a) were pooled, the equation of the best-fit curve could be computed (Fig. 4(b)). It could then be seen that healthy individuals were located on, or close to, the flat part of the curve (55%ST), whereas the current patients were on the steep part of the curve (40%ST). Identical computations for the SAT to %ST ratio gave corresponding estimates that the location of the current patients was on the steep part of the curve (Fig. 4(c)). It was also obvious from Fig. 4(b) and (c) that the SUQ and SAT values of the current patients were below and to the left of those of healthy individuals. In comparison with the best-fit curve, this suggested relatively depressed SUQ and SAT values in the patients.

To examine further the relationship between muscle UQ and plasma antioxidants, the ratios of SUQ and SAT to muscle oxidative fibers were related to MQI. It was then found that the SUQ and SAT ratios increased with increasing MQI, irrespective of %ST or %(ST + Fta) (Fig. 5(a) and (b)).

Neither UQ in muscle and blood nor plasma AT was directly or indirectly related to any of the exercise capacity variables.

DISCUSSION
The major findings in the present effort angina patients were:

( 1) muscle UQ per unit of oxidative muscle fibers (MQI) decreased as the individual proportion of oxidative muscle fibers increased;

( 2) plasma UQ was not related to muscle UQ but to plasma AT;

( 3) plasma antioxidants per unit of oxidative muscle fibers decreased with a decrease in the individual proportion of oxidative muscle fibers;

( 4) no exercise variable was directly or indirectly related 'to muscle UQ or plasma antioxidant levels.

It is suggested that muscle oxygen metabolism and the subsequent formation of free radical species were causally involved in regulating muscle and blood antioxidant activities. Whereas muscle UQ, MQI:%ST, plasma UQ and AT were no different from the corresponding values in healthy individuals, SUQ and SAT were depressed [ 21, 26].

The ratios of SUQ and SAT to vastus lateralis muscle %ST (plasma antioxidant quality indices) are 18.5 + 1.7 x 10-3 and 294 + 23 (multiply) 10-3 units on average in a healthy individual, which are no different from the present data [ 21, 26]. However, when the means were analyzed for muscle fibre type distribution, it was suggested that the current patients represented a stage of depressed plasma antioxidant status.

The 'normal' MQI and 'depressed' SUQ and SAT in the current patients, when related to %ST or %(ST q-Fta), might be confusing. In healthy individuals, peripheral resistance at rest and during exercise decreases with the oxidative ('aerobic') profile of the muscle. This enhances the availability of molecular oxygen and the radical threat in the contracting muscles [ 17].

The MQI computations based on %ST or %(ST+ Fta) decreased in the muscles examined for any expression of oxidative muscle fibre types. The same was true for SUQ or SAT when expressed as plasma quality indices. Moreover, MQI was dependent on plasma quality indices. Taken together, an increased proportion of oxidative muscle fibers resulted in lowered muscle and plasma antioxidant levels, indicative of increased radical trauma and turnover. The opposite is also true, i.e. an unpregulation of MQI follows a raised plasma UQ level [ 27, 28].

Formation of reactive radicals species, especially free oxygen radicals, during muscular exercise is confined to oxygen availability and turnover [ 29-31]. Oxidative muscle fibers (ST and Fta) and their mitochondria are the main site for these oxidative processes and the subsequent radical formation [ 18, 32, 33]. It is estimated that up to 15% of molecular oxygen turnover could result in radical formation [ 31, 34, 35].

The reduced forms of UQ (ubiquinol) and AT are the antioxidant active forms of these nutrients (antioxidant vitamins). With radical reactions they will become oxidized. Oxidized AT is decomposed and excreted, if not recovered and reduced [ 36]. Antioxidant reduction is the result of the mitochondria and their activity of feeding electrons into the antioxidant machinery. It seems plausible to assume the same pattern for UQ [ 37]. An enhanced radical pressure is then likely to induce a net depletion of these antioxidants in muscle and blood.

Both UQ and AT and their antioxidant properties have been known for a long time. Lack of them has been causally related to cardiovascular diseases, including ischemic disorders [ 6]. Epidemiological studies have given further support to this in relation to AT [ 38]. Clinical evidence has been presented that heart, skeletal muscle and plasma UQ are depressed in cardiovascular diseases [ 26, 39-41]. Controlled studies in patients with cardiovascular diseases have revealed the benefit of UQ therapy (nutratherapy)[ 42-44]. Nu-tratherapy with lipophilic antioxidant vitamins has been shown to increase UQ levels in tissues such as heart[ 45], skeletal muscle [ 28, 46] and blood [ 27, 42], and AT in plasma [ 47].

The exact nature of the UQ nutratherapy effects has not been fully elucidated. The antioxidant feature, as is true for AT, has been documented in animal experiments [ 6]. In humans, the antioxidant potential of UQ has been demonstrated in vitro with respect to lipoprotein protection against lipid peroxidation [ 48]. This has also been demonstrated with respect to AT [ 49]. In addition to the antioxidant effect, it seems reasonable to assume a beneficial effect of UQ treatment on the coenzyme Q( 10) activity of UQ in the mitochondria's adenosine triphosphate resynthesis [ 50, 51].

To summarize, patients with severe ischemic heart disease and effort angina have more depressed muscle and blood antioxidant activities the higher the oxidative potential in skeletal muscle. Data do not exclude the possibility of an impaired antioxidant activity being causally involved in radical-induced trauma to skeletal muscle and down regulation of peripheral oxygen metabolic activity, including the capillary network. The subsequent increased peripheral resistance might cause an advantageous increased systemic blood pressure, but also a reduced physical performance.

TABLE 1. Anthropometry and exercise capacity data in male effort
angina patients (n = 12) presented as individual values, means,
standard error of the mean (x + 1 SEM) and standard deviation (SD)
in parentheses

AGE HEIGHT WEIGHT BMI
Patient (years) (kg) (kg) (kg m- [sub]2)

I 60 170 66 22.8
II 67 180 80 24.7
III 57 172 76 25.7
IV 53 168 83 29.4
V 72 172 76 25.7
VI 58 178 81 25.6
VII 62 182 101 30.5
VIII 61 179 71 22.2
IX 56 172 80 27.0
X 67 181 89 27.2
XI 53 170 78 27.0
XII 62 181 87 26.6

Means 61 + 2 175 + 1 81 + 2 26.2 + 0.7
(6) (5) (9) (2.4)

W [sub]obla W [sub]sl W [sub]obla kg- [sub]1
Patient (W) (W) (W kg- [sub]1)

I 80 120 1.21
II 96 150 1.2
III 90 130 1.18
IV 95 150 1.14
V 92 100 1.21
VI 80 140 0.99
VII 50 0.5
VIII 60 110 0.85
IX 90 100 1.12
X 120 1.35
XI - 130 XII
95 130 1.09
Means 86 + 6 119 + 8 1.1 + 7
(19) (27) (0.23)

Peak blood lactate
Patient (mmol 1- [sub]1)

I 2.5
II 4.8
III 4.5
IV 4.9
V 2.3
VI 4.6
VII 1.4
VIII 3.1
IX 2.8
X 1.6
XI -
XII 3

Means 3.2 + 4
(1.3)

TABLE 2. Leg muscle properties. Muscle fibre composition is
expressed as the percentage distribution of slow twitch (%ST),
and .the sum %ST and the gast twitch (FT) fibre subgroup Fta
(%Fta), the `intermediate' fibre between the ST and FT fibre
populations (%ST+Fta). Ratio calculations (MQI) for muscle UQ
content to oxidative muscle fibre distribution (%ST or %(ST +
Fta)), and the same computations for standardized plasma
ubiquinone (SUQ) and alpha-tocopherol (SAT) are included. All
data are presented as mean + 1 SEM and with 1 SD in parentheses
(see Table 1).

Vastus lateralis muscle Gastrocnemius muscle

%ST %(ST + Fta) %ST %(ST + Fta)

Oxidative muscle fibre composition
37 + 4 74 + 9 59 + 5 79 + 7
(11) (23) (16) (19)

MQI x 10 [sup]3
6.47 + 1.02 3.06 + 0.24 3 + 0.55 2.75 + 0.44
(2.75) (0.68) (1.49) (3.89)

SUQ based ratio x 10 [sup]3
15.0 + 3.0 7.7 + 1.3 9.6 + 1.0 7.4 + 1.1
(8.1) (3.5) (2.7) (3.0)

SAT based ratio x 10 [sup]3
215 + 40 128 + 25 124 + 14 96 + 14

TABLE 3. Contents of UQ in blood and plasma, and AT and FC in
plasma. The individual plasma UQ and AT data are recalculated and
standardized (SUQ and SAT) for the average plasma FC content in
healthy individuals (0.6 g 1- [sup]1). All data are expressed as
mean + 1 SEM, 1 SD within parentheses (see Table 1) and range.

Blood UQ Plasma UQ Plasma AT Plasma FC
(mg 1- [sup]1) (mg 1- [sup]1) (mg 1- [sup]1) (g 1- [sup]1)

0.83 + 0.07 0.88 + 0.09 12.1 + 1.2 0.75 + 0.08
(0.19) (0.24) (0.65) (0.22)

0.35 - 1.14 0.32 - 1.48 4.4 - 20.4 0.29 - 1.34

SUQ SAT
(units) (units)

0.53 + 0.05 7.3 + 0.7
(0.14)

0.19 - 0.89 2.6 - 12.4
GRAPHS: FIG. 1. The individual relationships in the current effort angina patients between (a) plasma FC values and BMI or body weight, and (b) plasma UQ versus body weight.

DIAGRAMS: FIG. 2. Mean values + 1 SD for (a) plasma UQ and (b) AT standardized for FC in the current patients (0.6 g 1-1, [ 21, 26]) (SUQ and SAT) compared with the same means in healthy individuals [ 21, 26].

GRAPHS: FIG. 3. (a) The individual relationships in the vastus lateralis muscle between the computed MQI, i.e. the ratio of muscle UQ over muscle oxidative fibers, either %ST or %(ST + Fta), and individual muscle oxidative fibre composition (%ST or %(ST + Fta)). (b) MQI versus %ST for the vastus lateralis (VL) and gastrocnemius (G) muscles for the current patients and for healthy individuals (only VL) [ 4]. These functions were not different. The combined function for all observations is included in the graph. (c) Line of identity (y = x) analysis of MQI based on %(ST + Fta) for the gastrocnemius and vastus lateralis muscles.

GRAPHS: FIG. 4. (a) Ratio of standardized plasma UQ (SUQ) (Fig. 2) to muscle oxidative fibers (%ST or %(ST + Fta)) in relation to muscle oxidative fibers. The same computations for healthy individuals are also included based on published data [ 21, 26]. (b)The SUQ data in Fig. 4(a) were pooled and the best-fit curve was computed. The present %ST mean + 95% confidence interval (CI) and the corresponding data for age-matched healthy sedentary males [ 24, 25] were included. (c) The same computations as in Fig. 4(b) but for SAT.

GRAPHS: FIG. 5. Standardized plasma UQ (a) and AT (b) (Fig. 2) (SUQ and SAT) versus MQI based on %ST and %(ST + Fta) (Fig. 3(a)).

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JAN KARLSSON AND BJARNE SEMB( 2), ( 1)OBLA AB, PO Box 242, S-185 23 Vaxholm, Sweden; :Department of Thoracic Surgery, Karolinska Institute, Stockholm, Sweden

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