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1 A. C. Burton Vascular Biology
Laboratory, The aim of the
study was to address discrepant findings in the literature regarding
coupling between decreased functional demand during disuse and reduced
capillarity. We previously reported [K. Tyml, O. Mathieu-Costello, and E. Noble. Microvasc.
Res. 49: 17-32, 1995] that severe disuse of
rat extensor digitorum longus (EDL) muscle caused by a 2-wk application
of tetrodotoxin (TTX) on the sciatic nerve is not accompanied by
capillary loss. Using the same animal model, the present study examined
whether this absence of coupling could be explained in terms of
1) too short a duration of disuse
and 2) muscle-specific response to
disuse. Fischer 344 rats were exposed to either no treatment (control) or to 2- or 8-wk TTX applications. Fiber size, capillary density per
fiber cross-sectional area, and capillary-to-fiber (C/F) ratio were
determined by morphometry in the EDL muscle (control, 2- and 8-wk
groups) and in the superficial portion of medial gastrocnemius (Gas)
muscle (control, 2 wk). In both muscles, microvascular blood flow was
evaluated by intravital microscopy [red blood cell
velocity in capillaries
(VRBC)]
and by laser Doppler flowmetry (LDF). Regardless of duration of TTX
application or muscle type, TTX-induced disuse resulted in a
significant reduction of fiber area (44-71%). However, capillary
density increased in EDL muscle (both at 2 and 8 wk) but not in Gas
muscle. C/F ratio decreased in EDL muscle at 8 wk (18%) and in Gas
muscle (39%). This indicates that the effect on capillarity depended
on duration of disuse and on muscle type. VRBC and LDF
signal were significantly larger in EDL than in Gas muscle. Analysis of
change in capillarity vs.
VRBC suggested
that the outcome of disuse may be modulated by blood flow. We conclude that the duration of skeletal muscle disuse per se does not dictate capillary loss, and we hypothesize that discrepant findings of coupling
between functional demand and capillarity could be due to the
presence/absence of flow-related angiogenesis superimposed on the
capillary removal process during disuse.
capillary density; blood flow; atrophy; capillary damage; angiogenesis
SKELETAL MUSCLE RAPIDLY ADAPTS to a chronic increase in
functional demand by an increase in anatomic capillary
density (10, 11, 20). Much less is known about the
coupling between the microvasculature and a decreased functional
demand, such as that which accompanies muscle disuse and atrophy. In
frog muscle, we found a reduction in number of perfused capillaries and
increased capillary endothelial damage with muscle atrophy (27). Others have also noted a coupling between decreased muscle use and reduced muscle capillarity (2, 12, 13). In contrast, in a rat model of muscle
disuse [tetrodotoxin (TTX) superfusion of sciatic nerve for 2 wk], not only was the capillary network of the extensor digitorum
longus (EDL) muscle maintained, there was, in fact, some evidence of
angiogenesis in the disused muscle despite a 40.5% loss in muscle
weight (28). Similar observations of maintained microvasculature after
muscle disuse have been made in rat muscle that had undergone other
forms of disuse atrophy, including denervation, hindlimb suspension,
and space flight (7, 11, 18). The reasons for the discrepant responses
of the microvasculature to muscle disuse noted above are unclear. They
could arise from differences in the severity or duration of disuse or
from differences in responsiveness to metabolic or hormonal stimuli
among the muscles examined.
In a previous study (28), we used a 2-wk TTX model of disuse to produce
a severe atrophy in the rat EDL muscle. Surprisingly, no coupling
between decreased functional demand and reduced muscle capillarity was
observed. There were two possible explanations for this observation.
First, the 2-wk TTX application could have been too short a period for
this coupling to occur (28). Second, the effective functional
sympathectomy associated with TTX application could have masked this
coupling. Because TTX application elevated red blood cell velocity
(VRBC) in
capillaries (28), the resulting increased shear stress on the capillary
wall could have affected capillary structure by inducing angiogenesis
and thereby maintaining capillarity (4, 19).
Thus the overall aim of the present study was to specifically address
the surprising finding of lack of coupling between muscle use and
capillarity in terms of these two possibilities. The first objective
was to establish whether the occurrence of coupling depends on the
duration of disuse per se. The second objective was to determine
whether a coupling occurs when blood flow is not elevated after the
application of TTX. We pursued this objective on the basis of the
reports in the literature (5, 15) that mechanical
denervation causes differential effects on muscle blood flow among
different muscles and among portions of muscles. For example, flow to
the rat soleus muscle was reduced by denervation by nearly 90%,
whereas flow to the middle portion of the lateral head of gastrocnemius
(Gas) was unaffected (5). Apparently, flexor muscles like the EDL may
be more sensitive to sympathetic nervous influences than are the
antigravity ankle extensor muscles, such as the Gas (15). Our
preliminary experiments along these lines indicated that blood flow at
the surface of the medial portion of the Gas in rats was indeed not
elevated after 2-wk TTX application; this suggests that this muscle was
a purer model of disuse than was EDL (i.e., without the confounding
effect of increased flow). Accordingly, we hypothesized that, unlike
results in the EDL muscle, 2-wk TTX-induced disuse in the Gas would
result in coupling between decreased muscle use and reduced capillarity.
Animal preparation.
The animal protocol was approved by the Council on Animal Care at the
University of Western Ontario. Male Fischer 344 rats (2-4 mo old)
were divided into four groups. Rats in the first group (2wD,
n = 25) and the second (8wD,
n = 14) group were subjected to
unilateral disuse of the hindlimb muscles for 2 and 8 wk, respectively. Rats in the third group (2wC, n = 24)
and the fourth group (8wC, n = 16)
were subjected to no treatment and served as 2- and 8-wk time-matched
control groups for the 2wD and 8wD groups, respectively. Disuse was
achieved by superfusion of the right sciatic nerve with TTX, a
procedure described in detail previously (28). Briefly, after
pentobarbital sodium (Somnotol, MTC Pharmaceuticals; 65 mg/kg ip)
anesthesia was induced, an osmotic pump (2002 Alzet) was filled with a
TTX solution (300 µg/ml of saline), placed under the upper back skin,
and connected via tubing under the skin to the nerve. During the period
of disuse, the effect of TTX was verified by the absence of the
toe-spreading reflex on hindlimb elevation and by observation of the
animal's limping gait. At the time the animal was killed, confirmation
of the efficacy of TTX-induced disuse was obtained by means of
stimulation of the sciatic nerve above and below the nerve cuff. It was
observed that nerve transmission was blocked when stimulation was
performed above the cuff. The amount of TTX solution in one pump was
sufficient for 2 wk. Therefore, for each rat in the 8wD group, the pump
was replaced (while the animal was under Somnotol anesthesia) by a new
pump with fresh TTX solution after 2, 4, and 6 wk. In the present
study, we used nontreated rather than sham-operated rats (pumps filled
with saline) as controls. Our preliminary study (5 nontreated vs. 5 sham-operated rats for 2 wk) indicated that there was no difference
between these two groups in terms of the right EDL muscle weight
[104 ± 5 vs. 106 ± 2 (SE) mg], density of perfused
capillaries (CDper, 27 ± 1 vs. 25.2 ± 0.8 cap/mm), and blood flow [as
measured by laser Doppler flowmetry (LDF): 0.26 ± 0.02 vs. 0.29 ± 0.05 V]. Measurements were made by intravital methods described below.
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
Experimental protocol. To address the first objective (effect of duration of TTX-induced disuse), we used two approaches to determine capillarity (i.e., via intravital microscopy and histology) and blood flow [via intravital microscopy and LDF] in EDL muscles in the four groups. From video recordings of three randomly chosen fields of view in each muscle (field size, 1.05 × 0.78 mm) capillarity was analyzed in terms of the density of capillaries with moving (CDper) and stationary (CDstat) red blood cells. In practice, we counted capillaries visible at the muscle surface that crossed a perpendicularly drawn test line on the video monitor. Capillarity measurement from histological sections is described in the next section. In the three recorded fields, we also measured the VRBC, an index of blood flow, in randomly chosen capillaries (4 capillaries per field) by means of the flying spot technique (25). The second approach for assessment of microvascular flow was the LDF that provides a signal proportional to VRBC in capillaries found in a surface volume of ~1 mm3 (26). In practice, we measured this signal on-line in three randomly selected regions in the center part of the exposed muscle by using a LDF (model Pf 1d Perimed).
To address the second objective (differential response between EDL and Gas muscles), analysis of capillarity and blood flow was carried out similarly at the surface of medial Gas muscle in the 2wC and 2wD rat groups. At the end of the intravital experiment, the exposed muscle (either EDL or Gas) was dissected out, blotted to remove excess moisture, and weighed. In a separate subgroup (n = 5) in each of the 2wC and 2wD groups, both the right EDL and the right Gas muscles were prepared for light and electron microscopic examinations. In a separate subgroup (n = 5) in each of the 8wC and 8wD groups, the right EDL muscle was also prepared for light and electron microscopy.Light and electron microscopy. For morphometric analysis of capillarity, we followed a previously described procedure (28). The EDL muscle was fully exposed, superfused with glutaraldehyde fixative solution (6.25% glutaraldehyde in 0.1 M sodium cacodylate buffer) for 30 min, excised whole, and stored in the fixative solution in the refrigerator. In regard to the Gas muscle, the exposed surface (including the area analyzed by intravital microscopy) was superfused with the fixative solution for 30 min. At this time, a 1- to 2-mm-thick layer was sliced away from this surface, stored in the fixative solution, and refrigerated. The middle one-third along the length of the excised EDL and Gas muscles was then cut into small blocks, postfixed in OsO4, dehydrated in alcohol, and embedded in epoxy resin. Four blocks per muscle were analyzed. The fixative solutions and tissue processing were the same as used previously (17, 28). They lead to an adequate preservation of skeletal muscle ultrastructure (8) and a minimal amount of tissue shrinkage (14, 30).
Cross sections (1-µm thick) to the muscle fibers were cut on an LKB Ultratome III, stained with 0.1% toluidine blue solution, and analyzed by light microscopy. Morphometric measurements of fiber cross-sectional area (size of analyzed field, 135 × 190 µm) and of capillarity (size of field, 250 × 250 µm) were performed by light microscopy on sections, as described previously (14, 24). Specifically, capillary density [i.e., capillary number per fiber cross-sectional area, interstitial space excluded, or QA(0)] was measured by point counting with a 100-point test grid at a magnification of ×400. Fiber cross-sectional area [
(f)] and the mean
number of capillaries around a fiber (NCAF) were
measured with an image analyzer (Videometric 150, American Innovison)
at a magnification of ×1,360. On average, 14 ± 1 (SE) fields
were measured per sample to estimate
QA(0), 168 ± 26 fibers/sample
for (f), and 137 ± 25 for
NCAF (size of
field: 135 × 190 µm), yielding a SE of the vast majority of the
estimates of <10%. Capillary-to-fiber ratio,
NN(c,f), was computed as the product of QA(0)
and (f). The sharing factor was
computed as NCAF
divided by NN(c,f).
To assess capillary damage that may be associated with muscle atrophy
(27), ultrathin cross sections (50-70 nm) of the same samples of
EDL muscles (2wC, n = 5; 2wD,
n = 5; 8wC,
n = 3; 8wD, n = 3) and Gas muscles (2wC,
n = 5; 2wD,
n = 5) were contrasted with
uranyl acetate and bismuth subnitrate and were examined with a Zeiss 10 electron microscope. Capillary wall damage was assessed from these
sections at magnifications of ×8,000-12,500 by using the
same qualitative indexes (endothelial thickening, and increased size
and frequency of both cytoplasmic folding and projections) as used previously (27, 28).
Vascular responsiveness after TTX treatment. Because the loss of capillaries in atrophied muscle may be associated with a loss of reactive hyperemia after a short-term ischemia (28), we subjected rats in all groups to a complete 30-min hindlimb ischemia (i.e., a tourniquet tied above the right knee) at the end of the intravital experiment. After the tourniquet release, the peak postischemic level and the duration of hyperemia were measured from the center region of the exposed muscle (EDL or Gas) by the LDF.
Data analysis. Data are presented as means ± SE. They were analyzed by ANOVA and two-tailed t-tests statistics at P < 0.05, unless stated otherwise.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Morphology.
After the TTX application on sciatic nerve for 2 wk, rat body weight
was significantly less (8%) compared with the control (291 ± 9 vs.
267 ± 7 g in 2wC vs. 2wD group, respectively). Similarly, TTX
application for 8 wk resulted in a 13% difference in body weight (344 ± 8 vs. 299 ± 8 g in 8wC vs. 8wD group, respectively). The TTX
applications for 2 and 8 wk resulted in significant reductions in EDL
muscle weight (35 and 43%, respectively; Fig.
1) and in (f) (44 and 71%, respectively;
Fig. 2). Both of these reductions
established the presence of disuse in the EDL muscle. The TTX
application for 2 wk also decreased the Gas muscle weight by 53% (Fig.
1) and the (f) by 53%
(Fig. 2).
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Hemodynamics.
Systemic blood pressure in rats of the 2wC group was 124 ± 4 mmHg;
that of rats in the 2wD, 8wC, and 8wD groups did not differ. Based on
the intravital approach, the TTX treatments for 2 wk and for 8 wk
resulted in 36 and 50% increases, respectively, in the density of
perfused capillaries in the EDL muscle (Fig.
8, top).
In contrast, the same treatment for 2 wk yielded no significant change
in this density in the Gas muscle (Fig. 8,
bottom). This confirms the findings
from the histological approach that no increase in capillary density
occurred, despite a substantial atrophy of the Gas muscle. The close
correlation between the two approaches for capillarity assessment is
illustrated by Fig. 9. This figure shows an
~1:1 relationship between the square root of the anatomic density
(i.e., the density of capillaries predicted to be visible at the muscle
surface) and the actual measurement of visible capillaries (CDper + CDstat) in each group. It also
indicates that there was not an appreciable number of capillaries that
could not be visualized with the intravital microscopic approach (e.g.,
capillaries perfused with plasma only).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The overall aim of the present study was to address discrepant findings regarding coupling between the decreased functional demand during disuse and reduced capillarity. The first objective was to examine the effect of duration of TTX application on capillarity in the EDL muscle. We found that TTX application for 8 wk, but not for 2 wk, resulted in capillary loss during disuse. Thus duration of disuse may account for the coupling between decreased functional demand and reduced capillarity. The second objective addressed the hypothesis that the 2-wk TTX application reduces capillarity in the Gas muscle. Capillary per fiber number data in this muscle demonstrated capillary loss and thus established coupling between reduced demand and capillarity in this tissue at 2 wk. The 2-wk TTX data also indicated that, despite large atrophy in both EDL and Gas muscles, there was a differential response in capillarity to disuse.
Model of TTX-induced disuse.
The TTX model entails both muscle disuse and functional sympathectomy,
because application of TTX on the sciatic nerve blocks Na+ entry in both motor and
sympathetic nerves (16, 22). The present data (Fig. 1) confirm the
pronounced effect of TTX-induced disuse on EDL and Gas muscle weights
(23, 28). Although the TTX model produces severe atrophy in a short
time, the functional sympathectomy and the resulting elevated blood
flow at 2 wk may affect the capillarity response to muscle disuse.
Using two independent approaches to assess blood flow, we have
established that the TTX application yields a differential flow
response in EDL and Gas muscles (see 2wC and 2wD groups, Figs. 10 and
11), a finding consistent with an earlier study (5). Thus
the present study allowed us to examine the effect of disuse with and
without the confounding effect of elevated flow. The mechanism of the
differential flow response, which is unknown, may involve differences
in 
-adrenergic receptor sensitivity and/or density in the
vasculature (5). Future studies that examine the vascular response to
catecholamines in these two muscles could contribute to the elucidation
of the mechanism of differential flow response.
Effect of 2- and 8-wk TTX applications on EDL muscle. For short-term disuse, the reported increase in cross-sectional capillary density has been accounted for by muscle atrophy (7, 11). This indicates that the total number of capillaries within the muscle remained unchanged. In the present study involving TTX application at 2 wk, the increase in anatomic capillary density (Fig. 3, 2wC and 2wD groups) tended to be larger than the reduction in fiber area (Fig. 2). As in our previous study (28), this was due to a significant increase in the C/F ratio (Fig. 4) that suggests angiogenesis. This finding is surprising, because the opposite tendency, i.e., a capillary loss, was expected during disuse. The use of markers for angiogenesis (e.g., proliferating cell nuclear antigen), if positive, would provide conclusive evidence that the increase in C/F ratio was associated with growth of new capillaries in the EDL muscle.
On the basis of 1) the lack of significant rarefaction of capillary bed, 2) the negligible ultrastructural damage of the capillary wall, and 3) the maintained reactive hyperemic response, it appears that the rat EDL muscle microvasculature was remarkably resistant to changes during the 2-wk TTX-induced disuse. A possible mechanism for the maintenance of vascular structure and function could be a dissimilar rate of muscle fiber vs. capillary endothelium adaptation to disuse. For example, the rate of production of de novo contractile proteins could be reduced much more than that of endothelial structural proteins. In this regard, the only available information relates to muscles subjected to an increased load. Over a 30-day period of compensatory overload, Plyley and co-workers (20) recently showed that increases in the mean NCAF and in fiber area corresponded to similar half-lives of 10.1 and 11.2 days, respectively. Thus, in muscle undergoing increased use, the time course of muscle fiber and endothelial adaptation appears to be similar. This observation is at odds with the proposal of dissimilar rates to explain the maintenance of the microvasculature during the 2-wk disuse. In regard to the long-term disuse, the significant decrease in C/F ratio and NCAF with 8-wk TTX treatment (Figs. 4 and 5) is consistent with reports of greater capillary loss with increased duration of disuse (3, 13). Because VRBC was no longer significantly elevated at 8 wk (Fig. 10), the outcome of 8 wk of muscle disuse was not confounded by the effect of elevated flow due to functional sympathectomy. The pattern of increased VRBC at 2 wk and the subsequent decline toward the control level at 8 wk (Fig. 10) is similar to that noted for blood flow in a muscle-denervation model (9). In the face of unaltered systemic blood pressure, this pattern suggests an adaptation of vascular tone to reestablish normal microvascular perfusion after muscle disuse and/or functional sympathectomy.Comparison of EDL and Gas muscles after TTX application. Comparison of C/F ratios in EDL and Gas muscles in the 2wD groups suggests that duration of disuse alone was not solely responsible for loss of capillaries. Because the same duration of 2-wk TTX application caused increased as well as decreased capillarity (Fig. 4), it appears that coupling between decreased functional demand during disuse and reduced capillarity was muscle specific. Muscle fiber atrophy was larger in Gas than in EDL (Fig. 2; ANOVA of interaction between muscle type and TTX treatment). This raises the possibility that the differential response in capillarity (Fig. 4) depended on the degree of atrophy. In another model of disuse (hindlimb suspension), Desplanches and co-workers (6) found no change in capillarity in EDL with a smaller degree of atrophy (22%), but they found a large change in capillarity (49% reduction) in soleus muscle with large atrophy (63%). Data in the 8wC and 8wD groups (Figs. 2 and 4) show, however, that the degree of muscle fiber atrophy per se cannot account for the differential response, because the largest atrophy (71%) was not associated with the largest loss in capillarity.
One of the proposed mechanisms that link increased demand (muscle contraction) and capillarization is that of increased shear stress and blood-endothelial cell interaction during contraction-induced increased flow (4, 19). In the present study, the 2-wk TTX-induced disuse of the EDL muscle was associated with increases in both capillarity (Fig. 4) and VRBC (Fig. 10). As discussed below, we explored whether the same mechanism linking capillarization and flow could be operational in the present experiments. Figure 2 shows the degree of muscle fiber atrophy in all three experimental conditions. If capillary density changed only passively due to this atrophy, then one could directly predict this density on the basis of the degree of atrophy. For example, because the EDL muscle fibers atrophied by a factor of 1.783 after 2-wk TTX application, the predicted capillary density would be 1.783 × 821 (i.e., density in the 2wC group, Fig. 3) or 1,464 capillaries/mm2. We identified the difference between the measured capillary density (i.e., 1,871 capillaries/mm2 in the 2wD group; Fig. 3 top, left) and the predicted capillary density as "differential capillarity" (i.e., 1,871
1,464 = 407 capillaries/mm2). Figure 12
shows a dependence of differential capillarity on VRBC and suggests
that the outcome of disuse-induced change in capillarity may be
modulated by blood flow. A similar modulation during EDL muscle disuse
(peroneal nerve-crush model) was reported by Zaida and co-workers (29).
Capillarity increased after a chronic administration of prazosin that
is known to elevate blood flow (3, 29). Although other
as-yet-undiscovered factors [such as a differential
susceptibility to sympathectomy (15)] could also contribute to
the differential response in capillarity seen in EDL and Gas muscles,
the present data are consistent with the proposed mechanism that links
capillarity and flow (4). Clearly, studies where flow can be
experimentally manipulated during disuse must be carried out to further
substantiate this possible mechanism.
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ACKNOWLEDGEMENTS |
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We thank Peter Agey, Li Wu, Tina Demaral, Larnele Hazelwood, and Aurelia Bihari for technical assistance, and we thank Dr. Gordon Doig of the Dept. of Epidemiology and Biostatistics, The University of Western Ontario, for advice on the analysis and interpretation of the data.
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FOOTNOTES |
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The work was supported by the Heart and Stroke Foundation of Ontario, the National Science and Engineering Research Council of Canada, and the National Heart, Lung, and Blood Institute Program Project Grant HL-17731.
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. §1734 solely to indicate this fact.
Address for reprint requests: K. Tyml, Dept. of Medical Biophysics, Univ. of Western Ontario, London, Ontario, Canada N6A 5C1 (E-mail: ktyml{at}lhsc.on.ca).
Received 6 August 1998; accepted in final form 18 June 1999.
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
REFERENCES
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capillaries) in
disused EDL and gastrocnemius muscles on
VRBC in these
muscles. Differential capillarity was computed as difference between
measured QA(0) in disused muscle
and predicted anatomic density on the basis of density in control
muscle and degree of fiber atrophy. See
DISCUSSION for details. Line
represents a line of best fit through the 3 points.