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Departments of Health and Kinesiology and of Medical Physiology, Texas A&M University, College Station, Texas 77843; Department of Surgery, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212; and Departments of Anatomy and Physiology and of Kinesiology, Kansas State University, Manhattan, Kansas 66506
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Delp, Michael D., Changping Duan, John P. Mattson, and
Timothy I. Musch. Changes in skeletal muscle biochemistry and histology relative to fiber type in rats with heart failure.
J. Appl. Physiol. 83(4):
1291-1299, 1997.
One of the primary consequences of left
ventricular dysfunction (LVD) after myocardial infarction is a
decrement in exercise capacity. Several factors have been hypothesized
to account for this decrement, including alterations in skeletal muscle
metabolism and aerobic capacity. The purpose of this study was to
determine whether LVD-induced alterations in skeletal muscle enzyme
activities, fiber composition, and fiber size are
1) generalized in muscles or
specific to muscles composed primarily of a given fiber type and
2) related to the severity of the
LVD. Female Wistar rats were divided into three groups: sham-operated
controls (n = 13) and rats with
moderate (n = 10) and severe
(n = 7) LVD. LVD was surgically
induced by ligating the left main coronary artery and resulted in
elevations (P < 0.05) in left
ventricular end-diastolic pressure (sham, 5 ± 1 mmHg; moderate LVD,
11 ± 1 mmHg; severe LVD, 25 ± 1 mmHg). Moderate LVD
decreased the activities of phosphofructokinase (PFK) and citrate
synthase in one muscle composed of type IIB fibers but did not modify
fiber composition or size of any muscle studied. However, severe LVD
diminished the activity of enzymes involved in terminal and
-oxidation in muscles composed primarily of type I fibers, type IIA
fibers, and type IIB fibers. In addition, severe LVD induced a
reduction in the activity of PFK in type IIB muscle, a 10% reduction
in the percentage of type IID/X fibers, and a corresponding increase in
the portion of type IIB fibers. Atrophy of type I fibers, type IIA
fibers, and/or type IIB fibers occurred in soleus and plantaris
muscles of rats with severe LVD. These data indicate that rats with
severe LVD after myocardial infarction exhibit
1) decrements in mitochondrial
enzyme activities independent of muscle fiber composition,
2) a reduction in PFK activity in type IIB muscle, 3) transformation
of type IID/X to type IIB fibers, and
4) atrophy of type I, IIA, and IIB
fibers.
3-hydroxyacyl-CoA dehydrogenase; lactate dehydrogenase; malate
dehydrogenase
INTRODUCTION ONE OF THE PRIMARY CONSEQUENCES of heart failure is a
decrease in work capacity. Several peripheral mechanisms have been
proposed to account for this loss, including reductions in skeletal
muscle perfusion and abnormalities in muscle metabolism (17, 18). In
regard to the alteration in metabolism, several studies have shown that
decrements in muscle oxidative potential, fiber transformation, and
fiber atrophy occur in humans with heart failure (8, 12, 13, 15, 21,
27, 28) and in laboratory rats (2, 3) in which left ventricular (LV)
dysfunction after myocardial infarction (MI) was experimentally
induced. For example, Arnolda et al. (2) and Brunotte et al. (3) have
shown that LV dysfunction in rats lowers the activity of oxidative
enzymes from gastrocnemius-plantaris-soleus muscle homogenate without
influencing glycolytic enzyme activities. Furthermore, the reduction of
oxidative enzyme activities was related to the severity of the LV
dysfunction.
What is still unclear is whether LV dysfunction-induced reductions in
mitochondrial enzyme activities predominantly occur in muscles composed
of a given fiber type. For example, if heart failure primarily affects
muscle composed of a specific fiber type, then it is possible that
measurements of enzyme activities from calf muscle homogenates during
moderate LV dysfunction could mask subtle fiber-specific changes within
a given muscle. Correspondingly, a change in muscle oxidative capacity
with severe LV dysfunction may not be generalized to all muscle types
but may occur predominantly in a muscle of a given fiber type, such as
slow-twitch soleus muscle. Therefore, the purpose of this study was
threefold: first, to determine whether LV dysfunction after MI induces
changes in the activity of enzymes involved in glycolysis
[phosphofructokinase (PFK) and lactate dehydrogenase
(LDH)], terminal oxidation [citrate synthase (CS) and
malate dehydrogenase (MDH)], and METHODS The methods employed in this study were approved by the Kansas State
University Institutional Animal Care and Use Committee. The
investigation conforms with the National Institutes of Health (NIH)
Guide for the Care and Use of Laboratory
Animals [DHHS Publication No. (NIH) 85-23, Revised 1985, Office of Science and Health Reports, Bethesda, MD
20892].
-oxidation of fatty acids
[3-hydroxyacyl-CoA dehydrogenase (HADH)] in muscles composed of different fiber types; second, to determine whether LV
dysfunction induces fiber transformation or atrophy in muscles with
diverse fiber types; and, third, to determine whether the extent of
muscular alterations is related to the severity of the LV
dysfunction. The results demonstrate that moderate LV
dysfunction produces modest alterations in muscle enzyme activities,
whereas severe LV dysfunction induces
1) decrements in mitochondrial
enzyme activities (CS, MDH, and HADH) independent of muscle fiber
composition, 2) a reduction in PFK
activity in muscle composed predominantly of type IIB fibers,
3) transformation of type IID/X to
type IIB fibers, and 4) atrophy of
type I, IIA, and IIB fibers. In addition, changes in muscle oxidative
enzyme capacity, type IIB fiber composition, and atrophy of type I and
IIB fibers are related to the severity of the LV dysfunction.
dP/dt,
respectively). Immediately after ventricular pressure was
measured, the catheter-tip pressure manometer was removed and the
animal was given an overdose of pentobarbital sodium (100 mg/kg body wt
ip).
Tissue samples.
Immediately after the rats were euthanized, the heart, lungs, and
soleus, plantaris, and gastrocnemius muscles were quickly excised; the
gastrocnemius muscle was further separated into deep red, middle, and
superficial white portions (6, 17). The portions of gastrocnemius
muscle were frozen in liquid nitrogen and stored at 70°C for
determination of enzyme activities. The soleus and plantaris muscles
were cut in half through the midbelly region. One-half of each muscle
was frozen in liquid nitrogen and stored at 70°C for
subsequent determination of enzyme activities, and the other one-half
was frozen in melting isopentane (159°C) and stored at
70°C for subsequent histochemical determination of fiber
composition and fiber cross-sectional area (CSA).
Enzyme assays.
The frozen muscle samples were pulverized under liquid nitrogen, and
total cellular enzymes were extracted by homogenizing the muscle powder
in a cold extraction buffer (6, 23). The assay mixtures for PFK, LDH,
CS, MDH, and HADH were the same as previously described (4, 23). Enzyme
activities, expressed as micromoles per minute per gram of wet weight,
were measured spectrophotometrically in 1-ml assay mixtures at
30°C.
Histochemical analysis.
Previous analysis of single muscle fibers has demonstrated that
specific myosin heavy chains I, IIa, IId/x, and IIb correspond to the
histochemically defined fiber types I, IIA, IID/X, and IIB,
respectively (29). Therefore, these four fiber types were delineated by
myosin adenosinetriphosphatase (ATPase) histochemistry as previously
described (7, 9). Three serial transverse cross sections (8 µm thick)
near the midbelly portion of soleus and plantaris muscles were cut in a
microtome cryostat at 24°C, mounted on glass coverslips, and
air dried. Type I fibers stained dark after preincubations at pH 4.3 and 4.45 and very light after a formaldehyde pretreatment and
preincubation at pH 10.4; the reverse was true for IIA fibers. Type
IID/X and IIB fibers both stained very light at preincubation pH 4.3 and medium at preincubation pH 4.45, but IID/X fibers stained medium
after formaldehyde-alkaline pretreatment whereas IIB fibers stained
light.
In addition to the four "pure" fiber types (types I, IIA, IID/X,
and IIB), intermediate hybrid fibers (types IC, IIC, IIAD, and IIDB)
were also evident in plantaris muscle and to a much lesser extent in
soleus muscle (see Refs. 7 and 9 for staining pattern). These hybrid
fibers coexpress several myosin heavy chains (19). Type IC and IIC
fibers, the only hybrid fibers observed in soleus muscle, contain both
heavy chains I and IIa. Type IIAD fibers contain heavy chains IIa and
IId/x, and hybrid IIDB fibers contain heavy chains IId/x and IIb (19).
In all cases, these hybrid fibers made up only a small portion (<5%)
of the total number of fibers in both soleus and plantaris muscles.
When these fibers were categorized into one of the four fiber types,
type IC fibers were designated type I because this hybrid fiber
contains more heavy chain I than IIa (19). Conversely, hybrid IIC
fibers were counted as type IIA because they contain more heavy
chain IIa than I. One-half of the hybrid IIAD fibers were
designated as type IIA and the other one-half as type IID/X. Similarly,
one-half the hybrid IIDB fibers were counted as type IID/X and one-half as type IIB. Fiber CSA of hybrid fibers was not measured in this study,
but has been reported in a previous study (7).
Determination of muscle fiber composition and CSA.
Serial cross sections of muscles stained for myosin ATPase were
analyzed. All the fibers contained in each muscle cross section were
typed to determine the relative population of each fiber type. Muscle
cross sections were then divided into five evenly spaced regions.
Representative fascicles with fibers cut perpendicular to their long
axes were chosen from each of the regions for measurement of fiber
areas. Fiber CSA was measured from an outer diameter tracing with the
use of an Olympus image-processing and shape-analysis system (6). A
minimum of five fibers of each type were measured in each of the five
regions of the muscle. Therefore, in every muscle, fiber area for each
of the four fiber types was measured in 25-40 fibers. Similar
sampling techniques have been previously used to determine fiber
population and area (6, 7).
Determination of LV infarct size.
The heart and lungs were cleaned, blotted, and weighed after excision.
The right ventricle (RV) of the heart was separated from the LV and
septum and weighed. The LV (with the septum intact) was weighed and
placed in 10% Formalin for a minimum of 72 h. The LV was then cut into
four transverse sections from the base to apex in parallel with the
atrioventricular groove. The four sections of the LV were subsequently
dehydrated in alcohol and xylene and embedded in paraffin. Transverse
sections (7 µm thick) were cut, mounted, and stained with Masson's
trichrome stain from which hematoxylin was omitted to provide maximal
discrimination between fibrous areas of infarct and viable muscle.
These sections were magnified and projected, and the size of the
infarcted areas was determined by planimetry with a Digital Image
Analyzer (Carl Zeiss MOPS 3) according to the technique described by
Pfeffer and co-workers (20).
Data analysis.
Rats with MI were separated into two groups based on the measurements
of LV end-diastolic pressures (LVEDP). Rats with documented infarcts
and LVEDP >5 mmHg but <20 mmHg were classified as having moderate
LV dysfunction. Rats with documented infarcts and LVEDP >20 mmHg were
classified as having severe LV dysfunction. A one-way analysis of
variance was used to compare infarct size, body mass, RV mass,
RV-to-body mass ratio, LV mass, LV-to-body mass ratio, lung mass,
lung-to-body mass ratio, heart rate, mean arterial pressure, LV
systolic pressure (LVSP), LVEDP,
+dP/dt,
dP/dt, enzyme activity, fiber
composition, and fiber CSA among groups. Student-Newman-Keuls method was used as a post hoc test to determine the significance of differences among means. A general linear models
procedure was performed to determine the significance of relationships
between LVEDP and LV infarct size, muscle mitochondrial enzyme
activity, percentage of type IIB fibers, or CSA of type I and type IIB
fibers and whether these relationships were best expressed as linear or
quadratic equations. The 0.05 level was chosen for statistical
significance for all analyses.
RESULTS
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dP/dt were less in the two LV
dysfunction groups than in sham-operated controls; there was no
difference in these variables between the two LV dysfunction groups.
Enzyme activities. There were no differences in the activity of LDH among groups in any of the muscles studied (Table 2). However, the activity of PFK decreased in the white portion of gastrocnemius muscle from rats with moderate and severe LV dysfunction. The activity of mitochondrial enzyme CS was lower in soleus muscle of rats with severe LV dysfunction than in soleus muscles of control animals and rats with moderate LV dysfunction. In the red portion of gastrocnemius muscle, CS was lower in rats with severe LV dysfunction than in controls, and in the white portion of gastrocnemius muscle, CS was lower in rats with moderate and severe LV dysfunction compared with sham-operated controls. The activity of mitochondrial enzyme MDH was lower in the red and white portions of gastrocnemius muscle from rats with severe LV dysfunction relative to control rats. The activity of HADH was lower in the red portion of gastrocnemius and plantaris muscles of rats with severe LV dysfunction than in control animals and animals with moderate LV dysfunction.
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0.471), LVEDP and MDH activity in the red
(r = 0.6859) and white
(r = 0.5531) portions of
gastrocnemius muscle (Fig. 3), and LVEDP
and HADH activity in the red portion of gastrocnemius muscle (Fig.
4; r = 0.560). There was also a tendency
(P < 0.1) for increases in
LVEDP to be related to decreases in HADH activity in
plantaris muscle (Fig. 4; r = 0.331).
0.471.
y = 25.141 0.246x.
P < 0.05.
0.6859. y = 824.3 7.489x.
P < 0.01. B: r = 0.5531. y = 215.5 1.861x.
P < 0.01.
0.560. y = 18.4 0.25x.
P < 0.01. B: r = 0.331. y = 12.4 0.104x. P < 0.1.
Fiber composition and CSA. There were no differences in fiber composition between sham-operated controls and rats with moderate LV dysfunction in either soleus or plantaris muscles (Table 3). In addition, fiber composition was not different in soleus muscle among control rats and animals with moderate and severe LV dysfunction. However, in plantaris muscle of rats with severe LV dysfunction, there were ~10% fewer type IID/X fibers than in control rats and rats with moderate LV dysfunction. Correspondingly, there were ~10% more IIB fibers in plantaris muscle of rats with severe LV dysfunction than in controls and rats with moderate LV dysfunction. Regression analysis indicated there was a significant linear relationship between LVEDP and the percent increase in type IIB fibers in plantaris muscle (Fig. 5; r = 0.475).
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CSA of fibers in soleus muscle was not different between control rats and rats with moderate LV dysfunction (Table 4). In soleus muscle of rats with severe LV dysfunction, CSA of type I and IIA fibers was less than that in sham rats and rats with moderate LV dysfunction. In plantaris muscle, type I fibers were smaller in rats with moderate and severe LV dysfunction than in control animals, but there was no size difference in type I fibers between the two LV dysfunction groups. CSA of type IIB fibers in plantaris muscle from rats with severe LV dysfunction was less than in control animals and rats with moderate LV dysfunction. There was also a tendency (P = 0.07) for CSA of type IIA fibers in plantaris muscle of rats with severe LV dysfunction to be less than that of type IIA fibers in control rats. There was a significant linear relationship between LVEDP and the decrease in type I fiber CSA (Fig. 6; r =
0.645).
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0.645.
y = 2,119.8 33.633x. P < 0.01.
DISCUSSION
Numerous studies in the literature have shown that heart failure can
induce skeletal muscle abnormalities and dysfunction. The present study
demonstrates that moderate LV dysfunction in rats has little impact on
skeletal muscle; i.e., there were modest changes in glycolytic and
oxidative enzyme activities in one muscle section but no alterations in
fiber composition or fiber CSA. However, severe LV dysfunction resulted
in 1) reductions in the activity of
enzymes involved in terminal oxidation and -oxidation of fatty acids
independent of muscle fiber composition;
2) reductions in the activity of PFK
in muscle composed predominantly of type IIB fibers;
3) alterations in muscle fiber
composition; and 4) atrophy of type
I, IIA, and IIB fibers. In addition, the present study is the first to
demonstrate a linear relationship between the severity of LV
dysfunction and the decreases in mitochondrial enzyme activities (Figs.
2, 3, 4), increases in the percentage of type IIB fibers (Fig. 5), and
atrophy of type I fibers (Fig. 6).
LV dysfunction was induced in two groups of rats through MI. The degree of LV dysfunction, defined as an increase in LVEDP, correlated with the size of the MI (Fig. 1). In both of the infarcted groups, the animals were in a state of partially decompensated heart failure, based on the RV hypertrophy and increase in LVEDP (Table 1). Although there was a continuum in the severity of the heart failure among the infarcted rats, the separation of the LV dysfunction animals into two groups produced clear differences between moderate and severe heart failure. In the group of animals we refer to as having moderate LV dysfunction (infarct size = 45 ± 2% of the LV), RV-to-body weight ratio and LVEDP were higher than that in sham-operated controls. Rats we considered to have severe LV dysfunction had significantly larger MIs (59 ± 4% of the LV) than did animals in the moderate LV dysfunction group, and this was associated with greater RV hypertrophy, a higher LVEDP, and an elevation in the lung-to-body weight ratio, indicating congestive heart failure was induced in this group. Others (20) have similarly grouped rats according to MI size and shown that ventricular function is directly related to the extent of infarction.
The present study builds on previous observations that severe, but not moderate, LV dysfunction reduces mitochondrial enzyme activities of calf muscle homogenates (2, 3). The present study was in part performed to determine whether LV dysfunction-induced alterations in muscle are specific to muscles composed of a given fiber type or are generalized in muscles regardless of fiber composition. The data demonstrate that the decrease in oxidative capacity, as indicated by decreases in mitochondrial enzyme activities (CS, MDH, and HADH), is not specific to a particular fiber type but occurs in muscles composed primarily of type I fibers (soleus muscle), type IIA fibers (red portion of gastrocnemius muscle), and type IIB fibers (white portion of gastrocnemius muscle). Thus severe congestive heart failure diminishes the aerobic capacity of all types of fibers in both deep and superficial limb muscles. These findings are in close agreement with a recent report demonstrating that the succinate dehydrogenase activity of type I, IIA, and IIB fibers was lower in human muscle biopsy samples from patients with chronic congestive heart failure (15).
Although the changes in oxidative enzyme activities induced by moderate and severe LV dysfunction in the present study are similar to those previously reported in rats (2, 3), disparities exist with regard to glycolytic enzyme activities (2). Specifically, we observed a decrease in PFK activity in the white portion of gastrocnemius muscle from rats with moderate and severe LV dysfunction. From calf muscle homogenates, Arnolda et al. (2) observed no change in PFK activity. In addition, PFK activity in muscle biopsy samples from heart failure patients was not different from that from control subjects (13, 27). The reason for the disparity between the present study and others (2, 13, 27) is unknown but may be related to the fiber "purity" of the muscle samples. For example, the white portion of gastrocnemius muscle, the only muscle section showing a decrease in PFK activity, consists of 92% type IIB fibers (6). Neither the muscle homogenate (2) nor the biopsy samples (13, 27) had this degree of fiber homogeneity. Thus the decrease in PFK activity observed in both groups of infarcted animals in the present study may only be present or detectable in homogenous muscle composed predominantly of type IIB fibers.
We observed that severe congestive heart failure induces a shift in fiber composition, with a decrement in the portion of type IID/X fibers and an increase in percentage of IIB fibers in plantaris muscle (Table 3). In addition, there was atrophy of type I, IIA, and IIB fibers (Table 4). It was surprising that an increase in the activity of glycolytic enzymes did not accompany the increase in the percentage of type IIB in plantaris muscle. Perhaps increases in the proportion of type IIB fibers are offset by decreases in the activity of glycolytic enzymes in type IIB fibers, similar to the decrease in PFK activity occurring in the white portion of gastrocnemius muscle. Alternatively, the lack of a change in glycolytic enzyme activities may be related to the fiber atrophy occurring in the muscle.
The increase in the percentage of type IIB fibers and the fiber atrophy observed in the present study differs from that reported by Brunotte et al. (3). These investigators found no change in fiber composition or fiber size with heart failure in rats, although they did report a reduction in calf muscle weight. There are several possibilities that may account for the disparity between the two studies, such as differences in the muscles studied or differences in the techniques used to determine muscle fiber composition. For example, the histological fiber typing method employed in the present study enabled discrimination between type IID/X and type IIB fibers, whereas the method used by Brunotte and co-workers would classify IID/X fibers as IIB (see Ref. 6 for details). Thus a change in fiber composition from type IID/X to type IIB, which was observed in the present study, could not be detected.
Changes in muscle fiber composition and size have also been reported in patients suffering from chronic heart failure. For example, several studies have reported decreases in the percentage of type I fibers (8, 15, 27) and increases in the percentage of type IIB fibers (8, 13). In the present study, there was not a significant change in the percentage of type I fibers (Table 3), although in the plantaris muscle there were 36% fewer type I fibers in animals with severe LV dysfunction than in control rats or animals with moderate LV dysfunction. It is possible that longer periods of infarction may be required for the type I-to-type II fiber conversion to become evident in the rat. In addition to changes in fiber composition, atrophy of type I (12), type IIA (13), and type IIB (13, 27) fibers has also been reported in heart failure patients.
The underlying mechanism(s) inducing decreases in aerobic capacity,
fiber transformation, and fiber atrophy in skeletal muscle remains
uncertain. One possibility is that these muscle abnormalities are
secondary to reductions in physical activity. Support for this notion
comes from observations that exercise training ameliorates muscle
metabolic alterations from developing in rats with heart failure (3).
However, to our knowledge only one study has directly assessed physical
activity as a factor in the muscle alterations induced by heart failure
(26). Simonini and colleagues (26) measured cage activity in rats with
and without MIs and found that there was no difference in the activity
levels of infarcted rats and control animals. However, despite the lack
of a difference in activity between the groups, the LV dysfunction rats
still demonstrated decreases in muscle citrate synthase activity,
reductions in the portion of type I fibers, and reductions in mRNA for
-myosin heavy chains and
cytochrome-c oxidase.
These data suggest that inactivity is not obligatory for the
development of skeletal muscle abnormalities with heart failure.
Data from the present study also suggest inactivity alone is not responsible for muscle alterations that develop during heart failure. For example, there were reductions in the activities of oxidative enzymes in muscle composed predominantly of type IIB fibers (i.e., the white portion of gastrocnemius muscle). Muscles composed of IIB fibers are only recruited during high- intensity exercise (1, 6) and thus would remain inactive during normal cage activity. The reduction of mitochondrial enzyme activities in quiescent muscle suggests the involvement of other factors not directly related to physical activity.
A second possibility is that alterations in skeletal muscle perfusion may impact the size and metabolic characteristics of muscle fibers. Several studies have demonstrated that muscle blood flow is diminished by heart failure (cf. Ref. 18). For example, in rats with MIs, hindlimb muscle blood flow is reduced at rest and during exercise (17). However, the reduction in muscle blood flow is related to the degree of LV dysfunction. In animals with moderate LV dysfunction, muscle blood flow is not altered at rest but is lower than in sham-operated controls during exercise. In rats with more severe LV dysfunction, muscle perfusion is lower at rest and during exercise than it is in control and moderate LV dysfunction rats. Thus moderate LV dysfunction does not alter resting muscle blood flow (17), and this is associated with little or no change in the size and metabolic characteristics of the muscle fibers (Ref. 2; present study). On the other hand, resting muscle blood flow is compromised with more severe LV dysfunction, and this corresponds to a decrease in the oxidative potential of the muscle, increases in the proportion of type IIB fibers, and fiber atrophy. Whether decreases in muscle perfusion are causally linked to the development of muscle abnormalities remains to be determined.
There are a variety of other factors altered by heart failure that could also have a significant impact on muscle mass and phenotypic expression. For example, with heart failure there are systemic elevations of norepinephrine (10, 24), arginine vasopressin (24), endothelin (5, 14), and tumor necrosis factor (11). What role, if any, these compounds may have with respect to alterations in skeletal muscle with heart failure remains unclear at the present time. It should also be noted that alterations in the level of other biochemical factors such as prostaglandin E2, which can mediate proteolytic activity (25), glucocorticoids, which have a pronounced catabolic effect on skeletal muscle (22), and growth hormone could potentially contribute to the transformations that occur in skeletal muscle with heart failure. Whether these compounds play any role in regulating muscle mass or phenotypic expression during heart failure also needs further elucidation. Therefore, the changes in the neuroendocrine systems may contribute to the alterations in fiber size and composition found in the study.
One of the hallmark features of congestive heart failure is an intolerance to exercise. It appears evident that the decreased exercise capacity of individuals with heart failure is due, at least in part, to alterations in the characteristics of skeletal muscle. Reductions in mitochondrial enzyme activities with heart failure diminish the potential of muscle to utilize O2 and thus increase the reliance on anaerobic metabolism to support the energetic needs of active muscle. The conversion of the more oxidative and fatigue-resistant fibers to type IIB fibers would further bias skeletal muscle more toward anaerobic metabolism. This shift to greater dependence on anaerobic metabolism undoubtedly contributes to an earlier onset of fatigue during exercise. Fiber atrophy would also reduce the peak force muscle could generate. Thus the functional significance of heart failure-induced muscle alterations is a reduction in the ability of muscle to sustain high power outputs for prolonged periods of time.
In summary, the results demonstrate that moderate LV dysfunction
produces only modest alterations in muscle enzyme activities. Severe LV
dysfunction, which results in RV hypertrophy and increases in lung wet
weight and LVEDP, induces 1)
reductions in the activity of enzymes involved in terminal oxidation
and -oxidation of fatty acids independent of muscle fiber
composition, 2) reductions in PFK
activity in muscle composed primarily of type IIB fibers, 3) transformation of type IID/X to
type IIB fibers, and 4) atrophy of
type I, IIA, and IIB fibers. In addition, there is a linear relationship between the severity of the LV dysfunction and the decrement in mitochondrial enzyme activities, the increase in the
percentage of type IIB fibers, and the atrophy of type I fibers in
skeletal muscle.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the excellent technical assistance of Mark Smith.
FOOTNOTES
Address for reprint requests: M. D. Delp, Dept. of Health and Kinesiology, Texas A&M Univ., College Station, TX 77843-4243.
Received 11 December 1996; accepted in final form 19 May 1997.
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