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Original Studies |
Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, and The Central Arkansas Veterans Health Care System (P.A.K.), Little Rock, Arkansas 72205; and the Department of Medicine, Cedars-Sinai Medical Center, University of California School of Medicine (R.B.S., M.F.), Los Angeles, California 90048
Address all correspondence and requests for reprints to: Philip A. Kern, M.D., ACOS-Research, 151/LR, Central Arkansas Veterans Healthcare System, 4300 West 7th Street, Little Rock, Arkansas 72205. E-mail: kernphilipa{at}exchange.uams.edu
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Abstract |
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Introduction |
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Muscle is the primary tissue that controls glucose disposal (6), and previous studies have characterized many of the biochemical and histochemical features of muscle in insulin-sensitive and insulin-resistant subjects. Previous studies have observed that the capillary supply to muscle, expressed as the capillary/fiber ratio, was associated with insulin sensitivity (7, 8). In addition, the proportion of type I (red, oxidative) muscle fibers was associated with a higher level of insulin sensitivity, and conversely, insulin sensitivity was inversely related to the proportion of the glycolytic or low oxidative type IIb muscle fibers (8, 9, 10).
Obese subjects demonstrated a decreased proportion of type I muscle fibers, a corresponding increase in type IIb fibers, and an overall decrease in mitochondrial enzymes, suggesting a decrease in muscle oxidative capacity (8, 9, 11). In addition, several studies have demonstrated an inverse correlation between obesity or diabetes and capillary/fiber ratio (8, 12). Thus, these alterations in muscle in obese subjects may account for much of the insulin resistance of obesity. Insulin sensitivity is improved by exercise (13), and several studies have demonstrated parallel changes in biochemical and histochemical properties of muscle. An increase in capillary/fiber ratio following chronic exercise has been observed in several studies (14, 15). In addition, very intense endurance training led to an increase in the proportion of type I fibers along with a decrease in the proportion of low oxidative type IIb fibers (16).
Weight loss results in an improvement in insulin sensitivity, and hence, one would expect that weight loss would lead to changes in muscle that are associated with improved insulin sensitivity, such as an increase in capillary/fiber ratio and/or an increase in the proportion of type I muscle fibers. Although few studies have examined weight loss, one previous study examined seven subjects before and after a mean 16% weight loss and found no change in capillary/fiber ratio or fiber type, even though there was an increase in the glucose disposal rate (12).
This study examined the effects of weight loss and weight stabilization on muscle capillarization, fiber type, and succinate dehydrogenase (SDH), which is an indicator of muscle oxidative capacity. We found a consistent increase in capillary/fiber ratio and capillary density as well as an increase in muscle fiber SDH activity even though there was no change in the proportion of muscle fiber types.
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Subjects and Methods |
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All subjects were recruited from the Cedars-Sinai Medical Center
Weight Control Program. Characteristics of the subjects are shown in
Table 1
. All subjects had been weight
stable at the initial weight for at least 3 months before beginning the
study. The subjects were taking no medications; none of the subjects
had diabetes, and no subject had a blood triglyceride level above 4.5
mmol/L. Exercise histories were taken on all subjects both before and
after weight loss, and exercise was quantitated by estimating calories
burned per week. After an overnight fast, a muscle biopsy was
performed, and body composition was measured using bioelectric
impedance. The weight loss program was comprised of weekly behavior
modification classes, and the subjects consumed between 520–800
cal/day of a commercial dietary supplement (Health Management
Resources, Boston, MA). All subjects were encouraged to lose as much
weight as they could. When subjects had reached their goal weight, or
stopped losing weight, a refeeding process was begun, with a goal of
stabilizing the patient’s weight. After the patient had begun the
refeeding process and maintained the reduced weight for at least 3
months, the second set of studies was performed. Thus, the muscle
biopsy studies were performed at a steady state obese weight and at a
steady state reduced obese weight.
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Percutaneous biopsies of the vastus lateralis were performed at the midportion of the thigh (15 cm from patella) under local anesthesia using a needle biopsy technique (17, 18). Muscle samples (25–40 mg) were obtained from the same area of the thigh before and after the period of weight loss. The biopsy specimen was mounted on cork with embedding medium (OCT compound, Tissue-Tek, Miles Laboratories, Elkhart, IN), oriented for transverse sectioning (i.e. with fibers perpendicular to cork surface), and then rapidly frozen in isopentane, which had been cooled to its melting point by liquid nitrogen. The fresh-frozen muscle samples were stored at -80 C until analysis. For the assessment of muscle fiber classification, morphometry, capillarity, and quantitative enzyme measurements, serial cross-sections of the muscle sample were cut using a cryostat (Reichert-Jung, model 2800E) kept at -20 C.
Fiber type proportions
Serial muscle cross-sections of 10 µm thickness were stained for myofibrillar adenosine triphosphatase (mATPase) after alkaline (pH 9.6), and acid (pH 4.3 and 4.55) preincubations (19). One additional serial section was fixed in 2% paraformaldehyde at pH 7.4 for 2 min at room temperature and then preincubated at pH 9.6, in a modification of a previously described method (20). These various staining procedures allow the classification of human muscle fibers into several types, i.e. types I, IIa, IIx, and IIc. For each muscle sample, fiber-type proportions were determined from an analysis of 200–650 fibers within the entire cross-section. The histochemically determined fiber type was also verified immunohistochemically, with 95% or more correspondence between the mATPase-based classification and the major isoform of myosin heavy chain (MyHC) expressed in single muscle fibers (see also below).
Immunohistochemical identification of MyHC isoforms
As described previously, human muscle fibers that stain histochemically as type IIb fibers actually express MyHC 2X, and there is no evidence that human muscle expresses MyHC 2B (21, 22). Various anti-MyHC monoclonal antibodies (MAb) were used for the indirect immunoperoxidase identification of MyHC isoforms within single fibers. Serial muscle cryosections (10 µm thickness) matching the mATPase stains were dried at room temperature, fixed in cold acetone for 5 min, washed with phosphate-buffered saline (PBS) for 5 min, and incubated in 5% goat serum for 15 min at room temperature. Sections were incubated for 1 h at room temperature in one the following MAbs: A4.951 (dilution in PBS, 1:500) reacting with human MyHC 1 (ß/slow), N2.261 (1:750) reacting with human MyHC 1 and 2A, and A4.74 (1:50) reacting with human fast MyHCs (i.e. 2A and 2X). These mouse Mabs (IgG1) were raised from hybridoma cell lines obtained from American Type Culture Collection (Manassas, VA). Sections were rinsed with PBS (three times, 10 min each time) and exposed to peroxidase-conjugated secondary antibody (horse antimouse IgG; 1:200) for 30 min at room temperature. Control sections were exposed to secondary antibodies only. Sections were rinsed with PBS (three times, 10 min each time), exposed to ABC (Vector Laboratories, Inc., Burlingame, CA) reagent for 20 min at room temperature, and rinsed in PBS. Visualization was obtained after diaminobenzidene reaction (10 min) and nickel amplification. Sections were washed for 5 min, dehydrated, cleared, and mounted with Permount.
Fiber cross-sectional areas and relative interstitial space
Muscle fiber cross-sectional area was determined quantitatively from microscopic images of digitized muscle sections, using a computer-based image processing system. The latter is composed of a Leitz Laborlux S (Leica Corp., Rockleigh, NJ) microscope, CCD video camera system (model VI-470, Optronics Engineering, Goleta, CA), high resolution Trinitron color video monitor (model PVM-1343MD, Sony Electronics, Park Ridge, NJ), 486 DX-50 MHz PC with a Targa+ imaging board (Truevision, Inc., Indianapolis, IN) and Mocha image analysis software (v 1.20; Jandel Corp., San Rafael, CA). A microscope stage micrometer was used to calibrate the imaging system for morphometry. The cross-sectional areas of 100–200 individual fibers (i.e. sampled from those used in the analysis of fiber proportions) were determined from the number of pixels within manually outlined fiber boundaries. The relative interstitial space was determined by subtracting the cumulative fiber area from the total muscle cross-sectional area. Thus, the interstitial space refers to all nonmuscle space, which includes blood vessels, nerve branches, matrix proteins collagen, etc. The relative interstitial space was expressed as a percentage of the total muscle area.
Fiber capillarization
An acidic (pH 4.0) mATPase reaction was used to visualize capillaries surrounding individual muscle fibers from 10-µm thick serial cross-sections (23, 24). This technique has been validated by our group against other commonly used methods (i.e. amylase-periodic acid-Schiff) (25) and alkaline phosphatase (24). This ATPase method identifies only the arterial end of the capillary bed by staining the capillary endothelium. Furthermore, the mATPase technique used in this study does not distinguish between perfused and nonperfused vessels. Several indexes of capillarity were determined: 1) the capillary to fiber ratio, i.e. the total number of capillaries divided by the total number of fibers within the muscle section; 2) the capillary density, defined as the number of capillaries per mm2 muscle area; and 3) the number of capillaries per fiber (and per fiber type), i.e. capillary contacts per fiber, or the number of capillaries surrounding each fiber.
Single fiber SDH activity
Fiber oxidative capacity was determined by quantifying the activity of SDH (a key mitochondrial enzyme in the Krebs cycle) in individual muscle fibers. The methodology employed to quantitate SDH activity has been described in detail in previous reports (26, 27). Briefly, in the histochemical reaction for SDH, the progressive reduction of nitro blue tetrazolium (NBT) to an insoluble colored compound (a diformazan) is used as a reaction indicator. The reduction of NBT is mediated by H+ ions released in the conversion of succinate to fumarate. In a series of 6-µm thick sections, the incubation medium contained a large quantity of succinate (60 mM), and thus, the SDH reaction was not substrate limited. In other sections, succinate was absent from the incubation medium, so that the reduction of NBT in these sections was nonspecific. These sections are referred to as tissue blanks.
The concentration of NBT diformazan (NBT-dfz) deposited within a muscle
fiber was calculated using the Beer Lambert equation: [NBT -
dfz] = OD/(k x L), where OD was the optical density of the
muscle fiber measured at 570 nm (the peak absorbance wave length for
NBT-dfz), k was the molar extinction coefficient for NBT-dfz
(26, 478 mol/cm), and L was the path length (i.e. 6-µm
section thickness) for light absorbance. The OD of muscle fibers was
determined using a microdensitometric procedure implemented on the
computer-based image processing system. The video image was then
digitized (8-bit gray level resolution) into a matrix of 1024 x
1024 pixels (picture elements). The gray levels of the video scanner
were calibrated for photometry (OD units), using a series of neutral
density filters (0.004–2.00 OD units; Melles Griot, Irvine, CA).
During the SDH reaction, the formation of NBT-dfz in muscle fibers
increased linearly over a period of at least 7–9 min. In reactions
where succinate was absent from the reaction medium, there was
measurable staining (i.e. reduction of NBT), but the OD did
not change significantly across the same time periods. The tissue blank
OD also corresponded to the OD measured at time zero in reactions where
succinate was present in the medium. Based on these data, we justified
the use of a single end-point measurement of OD, with a reaction time
of 5 min. The reaction was stopped at 5 min by immediately rinsing
sections (both tissue blanks and those with succinate) with distilled
water. Sections were dried, mounted, and kept in the dark until images
were scanned and digitized (
2–3 h). In previous experiments, we
have determined that there were no significant changes in individual
muscle fiber OD values if sections were scanned/digitized within
10 h after the end of the SDH reaction.
From these end-point measurements, a rate of SDH reaction was interpolated. The mean SDH activity of individual muscle fibers was determined by averaging the OD of all pixels within outlined muscle fibers. To correct for the nonspecific formation of NBT-dfz, the tissue blank OD for each fiber was subtracted from the OD measured when substrate was added to the incubation medium. From the Beer-Lambert equation, the mean SDH activity of each fiber was expressed as mmol fumarate per L tissue/min. Approximately 100–200 fibers (i.e. same fibers sampled for the measurement of cross-sectional area) were analyzed for SDH from each specimen. The SDH activity of each individual fiber was used to determine the mean SDH activity for each fiber type. Based on the relative contribution of different types of fibers to total muscle cross-sectional area, the mean total SDH activity was also determined for each muscle sample.
Statistics
All data were expressed as the mean ± SEM. Before and after weight loss data were analyzed nonparametrically using the Wilcoxon sign-rank test, and linear regressions used Pearson product-moment correlations.
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Results |
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shows the characteristics of the subjects before and after
undergoing weight loss. The initial body mass index (BMI) ranged from
28.0–41.3, and subjects lost 19.9 ± 2.3 kg, which represented
20.8 ± 2.1% of the initial body weight. Subjects had muscle
biopsies from the vastus lateralis before the weight loss and 3 months
after weight stabilization and resumption of an eucaloric diet. Fiber types, cross-sectional areas, and relative interstitial space
From the muscle biopsy specimens, muscle fibers were identified
histochemically and immunohistochemically and were classified as type
I, type IIa, or type IIx. Figure 1 is a
representative series of adjacent sections demonstrating the
identification of muscle fiber type using both the histochemical and
the immunohistochemical methods. As shown in Fig. 1, identical results
were obtained with the identification of fibers as type I, type IIa,
and type IIx. Using both methods to identify muscle fiber type
proportions, muscle fiber typing was performed in each patient both
before and after weight loss. As shown in Fig. 2A, there was no change in the
proportions of the fiber types after weight loss. The mean percentage
of type I fiber in the subjects was 45.8 ± 2.8% when obese and
46.4 ± 2.2% when reduced obese. In addition, there was no change
in mean muscle fiber cross-sectional areas for each type of fiber
before and after weight loss (Fig. 2B). Taking into account the fiber
proportions and cross-sectional area of fibers, we estimated the
relative contribution of specific fiber types to total muscle area and
found it to be unchanged after weight loss (data not shown). However,
assessment of the relative proportions of interstitial space and muscle
area revealed that, after weight loss, the cumulative muscle fiber area
increased, whereas the relative interstitial space decreased
significantly from 8.6 ± 0.3% to 7.4 ± 0.3%
(P < 0.05).
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Muscle fiber capillarization was measured in these subjects before
and after weight loss, and several indexes of capillarity are shown in
Table 2. As shown in Fig. 3, there was a significant increase in
capillary contacts per fiber with weight loss in all subjects and in
relation to all fiber types. As shown in Table 2, the mean number of
capillaries contacting individual muscle fibers was increased, and this
was also observed in each individual fiber type. The number of
capillaries around types I, IIa, and IIx in the vastus lateralis
increased significantly by 13%, 10%, and 5%, respectively, after
weight loss (P < 0.05 for each). The capillary/fiber
ratio, the capillary density, and the mean number of capillary contacts
per fiber increased significantly by 32%, 54%, and 10%,
respectively, in the vastus lateralis after the period of weight loss
(P < 0.05). Together, these data are consistent with
an overall increase in the number of capillaries in vastus lateralis
after weight loss.
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Muscle oxidative capacity was assessed by measuring the rate of
SDH activity within individual muscle fibers. As shown in Fig. 4, weight loss resulted in an increase in
SDH activity that occurred in the most oxidative type I fibers (41%)
as well in type IIa (36%) and IIx (33%) fibers (P <
0.05). Total SDH activity in the vastus lateralis was measured based on
the mean SDH activity of each fiber type and the relative contribution
of each specific type to the total muscle area (see above). Total SDH
activity in the muscle samples was 1.51 ± 0.21 mmol fumarate/L
tissue·min) in the obese subjects and 2.10 ± 0.29 in the
reduced obese subjects (i.e. a 39% increase in SDH
activity; P < 0.05). In addition, the increase in
total SDH activity in the muscle samples correlated significantly with
the change in capillary/fiber ratio (Fig. 5). Thus, subjects who demonstrated the
largest increase in capillary/fiber ratio also demonstrated the largest
increase in muscle SDH activity.
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100
cal/day), whereas others did not exercise at all. Nevertheless, there
was no significant correlation between the amount of exercise or the
change in exercise habits and any metabolic property of muscle.
Specifically, a change in exercise habits bore no correlation to change
in capillary/fiber ratio, SDH activity, or fiber type. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Compared to the muscle biopsy samples from the obese state, the reduced obese muscle samples demonstrated the same proportion of type I, type IIa, and type IIx fibers. There was no change in the mean cross-sectional area of individual fibers for all three muscle fiber types, whereas there was a small, but significant, decrease in the relative interstitial space. As a greater area of the muscle was occupied by muscle fibers after weight loss, this could translate into an increase in muscle specific force (i.e. force produced per unit area). Although there was no change in fiber type, there was a consistent increase in the oxidative capacity of each muscle fiber type along with a consistent increase in the capillary/fiber ratio and capillary density. In addition, the changes in capillary/fiber ratio closely paralleled the changes in muscle SDH activity.
Weight loss is known to result in an improvement in insulin sensitivity (4, 5). Subjects that are more insulin sensitive tend to have an increased proportion of type I muscle fibers, a higher capillary/fiber ratio, and higher muscle oxidative enzyme activity (7, 8, 9, 10). Some studies have also demonstrated a relationship between fiber type and some measure of central adiposity (8, 10, 28, 29), suggesting that muscle fiber type is part of the metabolic syndrome characterized by central adiposity, insulin resistance, hypertension, and dyslipidemia (30). Although one would expect an increase in insulin sensitivity with the weight reduction reported herein, measurements of insulin sensitivity were not performed. Hence, this study cannot determine whether the changes in muscle capillarization were associated with changes in insulin sensitivity.
There are a number of possible explanations for the changes observed in these subjects. The prolonged period of weight loss that these subjects experienced is characterized by relative hypoinsulinemia, hyperglucagonemia, and elevated nonesterified fatty acids (NEFA), which are released by adipose tissue and are eventually metabolized by muscle. Any one of these circulating hormones or substrates may be a driving force to increase muscle oxidative capacity. As the oxidative capacity of muscle fibers represents their ability to metabolize NEFA, it is interesting to speculate that the chronically elevated NEFA represents a substrate-driven change in muscle oxidative capacity. However, relatively few studies have examined subjects before and after weight loss, and one should not assume that reduced obese subjects are metabolically identical to subjects who were never obese. In one study where reduced obese and lean women were compared, the reduced obese women demonstrated decreased levels of some oxidative enzymes (31).
Although weight loss resulted in changes in oxidative capacity and capillarization, there was no change in muscle fiber type. This discordance between change in fiber type and oxidative capacity is interesting and contrasts with the increase in type I fibers seen in lean subjects in cross-sectional studies (8, 9, 11). Fiber type is determined by the isoforms of myosin and their ATPase. Although prolonged and intense endurance training can result in an increase in the proportion of higher oxidative (type I and type IIa) muscle fibers (16), the proportion of muscle fiber types is largely under genetic control (32) and less subject to change. Because others have noted an association between muscle oxidative capacity and waist/hip ratio or other measures of abdominal adiposity (8, 10, 28, 29), it is interesting to speculate that a low oxidative capacity of muscle is part of the phenotype of the metabolic syndrome (syndrome X) (30).
It would be of interest to examine the effects of weight loss on other muscles in addition to the vastus lateralis. The vastus lateralis is the usual site chosen for studies of human muscle, mainly because of the ease of biopsy, but also because it is composed of a mix of both slow and fast fibers. In one study that related muscle oxidative capacity to insulin sensitivity, vastus lateralis muscle oxidative capacity correlated with insulin sensitivity, whereas no such changes occurred in gastrocnemius muscle (33). Thus, it appears that vastus lateralis is a good representative muscle for these studies.
In summary, we examined fiber type, fiber size, SDH, and capillarization of vastus lateralis muscle from obese subjects before and after weight loss. Weight loss resulted in increases in capillarization and oxidative capacity in all fiber types, but without a change in the proportions of the different fiber types and their individual cross-sectional areas. These studies provided new insight into the mechanisms underlying the insulin resistance of obesity.
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Acknowledgments |
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Footnotes |
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2 Current address: Cnel. Niceto Vega, 4871 2:6, 1414 Buenos Aires,
Argentina.
Received March 4, 1999.
Revised May 24, 1999.
Accepted July 12, 1999.
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