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*
Department of Cell Biology and Physiology,
**
Magee Women’s Research Institute,
Children’s Hospital of Pittsburgh, and
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • cachexia • Fischer 344 rats • senescence • undernutrition
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 1999
,
McCarter et al. 1982
, Prezant et al. 1994
), muscle disuse (Carmeli et al. 1993
,
Evans and Campbell 1993
) and aging (Corpas et al. 1992
, Evans and Campbell 1993
, Larkin et al. 1998
, Proctor et al. 1998
). Muscle atrophy
in elderly patients may be especially pronounced with certain diseases
that are accompanied by cachexia (Donahoe 1997
,
Pape et al. 1991
, Wolf et al. 1992
), which is characterized as poor health accompanied by
emaciation. The cachectic state is considered to be a function of poor
nutrition either due to appetite suppression or an inability to feed
properly (Donahoe 1997
). In these instances, muscle
atrophy can be due to sarcopenia or a loss of muscle mass associated
with negative protein balance and persistence of a catabolic state
(Clemmons and Underwood 1992
, Donahoe 1997
, Evans and Campbell 1993
, Proctor et al. 1998
). This situation is poorly responsive to nutritional
repletion (Donahoe 1997
). Thus, supplementation of
nutritional repletion with anabolic hormones such as growth hormone
(GH)3
has been considered (Clemmons and Underwood 1992
, Donahoe 1997
, Pape et al. 1991
, Wolf et al. 1992
), however, the specific
effects of GH on muscle phenotype and function in the setting of aging
and chronic undernutrition (UN) remain incompletely understood. A prior
report indicated that GH administration in conjunction with nutritional
repletion reversed some of the alterations produced by UN within the
aged diaphragm muscle (Ameredes et al. 1999
), therefore,
GH effects on aged limb skeletal muscles would seem likely.
Moreover, the signals for these alterations in skeletal muscle
phenotype are not known with certainty, particularly with UN in the
context of aging. It is known that sarcopenia is associated with
age-related decrements in function of the thyroid axis
(Lamberts et al. 1997
) and the pituitary-gonadal
axis (Lamberts et al. 1997
, Tenover 1997
). Especially in males, decrements in circulating androgens
such as testosterone and associated decreases in growth factors occur
with UN (Lanz et al. 1992
) and aging (Everitt and Meites 1989
), but have not been linked conclusively to the
muscle atrophy process (Lamberts et al. 1997
,
Proctor et al. 1998
, Tenover 1997
).
Interestingly, many of these same events occur with simple
food-restriction, which traditionally has been considered to retard
or postpone the aging process (McCarter et al. 1982
,
Sojal and Weindruch 1996
). This dilemma may have serious
ramifications with regard to nutritional and hormonal treatment of aged
cachectic patients who require these therapies to assist in the
management of their disease. Thus, further understanding of these
effects is desirable.
Therefore, the purpose of the following study was to determine the alterations in mammalian muscle phenotype under conditions of severe chronic UN, followed by nutritional repletion through refeeding (RF), and administration of GH. Physical characteristics and myosin heavy-chain (MHC) composition of selected prototypical fast (extensor digitorum longus), slow (soleus) and mixed (gastrocnemius) limb muscles were measured. Changes in circulating testosterone under these conditions were assayed as one possible signal in the trophic processes. The hypothesis tested was that GH, in combination with refeeding, would reverse the muscle atrophy and MHC shifts induced by chronic UN, and that these alterations would be associated with changes in circulating testosterone levels.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The animal care and nutrition protocol was approved by the University
of Pittsburgh Institutional Animal Care and Use Committee and conformed
to the NIH guidelines (Guide for the Care and Use of Laboratory
Animals, NIH Publication No. 86–23). Briefly,
adult male Fischer 344 rats were given free access to a standard diet
of Purina Rat Chow and weighed twice per week over the course of a 9-mo
period from the delivery
date.4
At this time they achieved a level of ~375 g body weight,
at 11 mo of age. Just prior to reaching this time interval, the average
daily food consumption (ADFC) for each rat was measured over a period
of 1 wk. One month later, the rats were placed randomly into
one of two feeding groups: a control group (n = 20), with free access to food throughout the remainder of the study,
and a UN group (n = 30), fed 50% of their ADFC for
a period of 7.5 mo. At the end of this 7.5-mo period, the UN group was
further partitioned into three groups. One group was refed with free
access to food for the remainder of the study (RF, n
= 10), while a second group was administered growth hormone
(Protropin®; Genentech, San Francisco, CA), injected i.p.
(1 mg/d) and was refed (RF + GH; n = 10), for the
remainder of the study. This dose was chosen based on a study in which
1 mg/d of GH was found to produce increases in refed rat diaphragm
muscle-type IIB and IIX fiber cross-sectional area, and a
significant increase in circulating insulin-like growth factor I
(IGF-I) (Lanz et al. 1992
). Average food consumption per
rat at 24 mo of age ranged from 14 to 19 g/d in control, RF and RF + GH
groups. Muscles were sampled at 19.5 and 24.5 mo of age as described
below with the end-point of the study being 24.5 mo of age, chosen
in part because it fell within a time (21–26 mo of age) when Fischer
344 rats are considered senescent (Yu et al. 1985
).
Unequal sample numbers were obtained for some muscles and measurements
due to their use in other studies.
Surgical.
Rats were anesthetized with pentobarbital sodium (30 mg/kg, i.p.) and
shaved. Through a midline incision of the abdomen, the diaphragm muscle
(DIAm) was excised surgically, en bloc, and cut into two
hemi-diaphragms. One hemi-diaphragm was trimmed of bone, fat
and connective tissue, and then was blotted, weighed and
snap-frozen in liquid nitrogen-cooled isopentane, and stored at
-80°C for later MHC analysis. The other hemi-diaphragm was
utilized for studies described elsewhere (Ameredes et al. 1999
). The extensor digitorum longus (EDLm), soleus (SOLm) and
gastrocnemius (GSTRCm) muscles were surgically excised from the lower
limb, blotted and weighed. They were snap-frozen in liquid
nitrogen-cooled isopentane and stored at -80°C for later MHC
analysis. During these procedures, the animal was killed under
anesthesia with a combination of exsanguination by blood withdrawal and
pneumothorax due to opening of the chest.
MHC and protein analyses.
MHC isoform composition analyses were performed on muscle homogenates
from individual rats in each group. MHC isoforms were separated from
myosin extracts by polyacrylamide gel electrophoresis (Fig. 1
) as previously described (Ameredes et al. 1998
a).
Briefly, gels were prepared from a stock solution of 30% acrylamide
containing 2.94 g/L of acrylamide and 0.06 g/L of bis
(N,N'-methylene-bis-acrylamide). Electrophoresis was
performed using a separating gel of Tm =
8% and stacking gel of Tm = 4%,
[Tm = total concentration of monomer
(acrylamide + bis)] at C = 2% (C = percentage of total
monomer due to bis). Volumes of myosin extract (1–3 µL) containing
500-1000 ng of protein per well were loaded on the gels.
Electrophoresis (275 V for 3.5 h then 178 V for 17.5 h) was
performed using a vertical slab gel unit (SE600; Hoefer Scientific
Instruments, San Francisco, CA) with Tris/glycine running buffer in a
cold room maintained at 4°C. Separating gels were silver-stained.
MHC gels were analyzed using a scanning densitometer (GS 300; Hoefer
Scientific, San Francisco, CA) and densitometry software (GS 365;
Hoefer Scientific) to quantify the area under individual isoform peaks.
These data were used to determine the relative contributions of
individual isoforms to their respective total MHC complements within
the muscle. Total protein concentrations were measured on separate
samples of muscle homogenates using the method of Lowry et al. (1951)
.
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Circulating testosterone levels were measured in blood samples taken
from the abdominal aorta. A 25-gauge angiocatheter was inserted just
above the renal artery bifurcation, advanced 2–3 mm and tied in place
with sutures previously placed around the vessel. One to two
milliliters of blood were withdrawn, centrifuged (3000 x g) and separated. Serum was frozen at -80°C for later
analysis. Duplicate serum samples for each rat were analyzed for total
testosterone levels using an 125I radioimmunoassay kit
(Coat-a-Count; Diagnostic Products Corp., Los Angeles, CA). The
sensitivity of the kit was 
0.14 nmol/L and the specificity for
testosterone was 95%.
Statistics.
Repeated-measures ANOVA (SigmaStat v.1.03; Jandel Corp., San Rafael, CA) was used to compare changes in body weight over the age interval studied with P < 0.05 considered significant. One-way ANOVA was used to compare muscle weight and MHC composition values within and between treatments at ages of 19.5 and 24.5 mo with P < 0.05 considered as significant. The general linear model of these ANOVA allowed compensation for unequal sample numbers between groups through sample number weighting of expected mean square values calculated for each group. Student-Newman-Keul’s posthoc test was used to compare these variable values between discreet groups at a significance level of P < 0.05. Thus, statistical significance is reported as P values <0.05 for all tests. When a significant ANOVA F statistic was obtained, but an apparent discreet trend was nonsignificant by posthoc testing, the P value is reported as >0.05. When other trends appeared to be present, but the ANOVA F statistic was nonsignificant, it is given as the "ANOVA P."
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Average body mass of both RF and RF + GH groups were significantly
greater than the UN group by the second week of their initiation (20.75
mo of age). Body mass in the RF + GH group was significantly greater
than RF beginning at 21.75 mo of age, becoming not different than
controls by 22.25 mo of age. At this time, body mass with RF alone was
still significantly lower than the controls and remained less than the
RF + GH group for the duration of the study.
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) were significantly lower in UN rats (P < 0.05). Both
RF and RF + GH produced significant increments, restoring mass toward
that of control, however, RF + GH increased both the body mass and the
GSTRCm mass to values above that of the RF group (P < 0.05). This trend also was suggested in the DIAm
(nonsignificant).
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) with RF and RF + GH resulting in significantly greater amounts of
protein in this muscle. The superficial GSTRCm showed similar trends
which did not reach statistical significance (ANOVA, P
= 0.80). No demonstrable alterations were observed for the EDLm
and SOLm.
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). At 19.5 and 24.5 mo of age, Type IIA MHC of the hemi-diaphragm
was increased while type IIX was decreased with UN at 19.5 mo of age
(Table 3
). These trends were suggested at 24.5 mo of age but did not reach
statistical significance (Type IIA: ANOVA P = 0.09,
Type IIX ANOVA P = 0.053). RF + GH significantly
decreased Type I and IIA MHC as compared to UN (P
< 0.05). A significant increase in Type IIX MHC was observed with
RF alone, and a similar increase was suggested with RF + GH, which did
not reach statistical significance (ANOVA P = 0.053).
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), while type IIB and IIX MHC were significantly decreased
(P < 0.05). RF and RF + GH reversed these shifts
to levels not different from controls. At this same age, percentages of
type I (P > 0.05), IIA (P < 0.05), and IIX (P < 0.05) MHC were less, while
type IIB MHC was significantly greater in the superficial GSTRCm with
UN. RF and RF + GH typically reversed these shifts, again restoring
respective MHC isoform levels toward those of the controls. An effect
of aging on MHC composition was observed between 19.5 and 24.5 mo of
age in the control superficial GSTRCm with a significant increase in
type I and IIA MHC and a decrease in type IIB MHC over time
(P < 0.05; main factor: time).
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). UN at 19.5 mo of age depressed testosterone levels to nearly zero. A
similar depression was observed with UN at 24.5 mo of age, however it
was not statistically different from the respective age-matched
controls (P > 0.05). Both RF and RF + GH resulted
in significantly greater levels of circulating testosterone as compared
to that in the UN rats.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The body mass of rats was dramatically lower with UN, attaining a value
of one-half that of freely-eating controls. The effect was
manifest early (within 2 wk), reaching a sustained plateau within about
5 mo. Initiation of RF and RF + GH resulted in rapid replenishment of
body mass with the RF + GH group demonstrating a greater and sustained
increment (Fig. 3)
. Moreover, the RF + GH group attained the control
body mass value by 21.25 mo of age, which was 2.5 mo more rapid than RF
alone. As shown in Table 4
, limb and respiratory muscle masses at 24.5 mo of age with UN were
approximately one-half that of respective controls. These data
indicated that the UN/control ratios of both body and muscle mass
attained values similar to the ratio of UN/control food provision
(~0.50). Subsequently, the overshoot of body and GSTRCm mass, along
with the trend in the DIAm, were suggestive of a hypertrophic effect of
GH when administered with RF. Thus, the relative masses of these two
muscles followed changes in the body mass under these conditions. These
findings demonstrate the ability of this nutritional/hormonal paradigm
to produce significant muscle atrophy and hypertrophy over a time span
that encompasses nearly the whole adult life of the rat.
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The significant decreases in protein concentration with UN and the
subsequent increases with RF and RF + GH in the deep GSTRCm suggest
that it was most affected by the experimental regime in this study.
While the protein values suggested increase with RF + GH vs. RF alone,
this increment was not statistically significant. Interestingly, the
superficial GSTRCm, comprised of mostly fast Type IIB and IIX MHC, was
not significantly affected, similar to the results seen with the EDLm,
which is a prototypical fast-fibered muscle. These results suggest
that protein turnover rates may have been most affected in largely
mixed-MHC muscles, i.e., those in which one MHC type does not
dominate the total MHC composition. Furthermore, this notion is
consistent with a prior study (Kelly et al. 1984
)
reporting protein turnover rate to be slowest in muscles with
predominantly fast-twitch fibers and higher in muscles such as the
medial GSTRCm and DIAm that have substantial mixed fast and slow fiber
composition. In the present study, the profound muscle atrophy with UN
and subsequent hypertrophy with RF + GH observed in the GSTRCm
(Fig. 2
) are likewise consistent with these ideas.
MHC shifts.
MHC shifts were most pronounced in the GSTRCm. As with the protein
concentrations, the alterations in MHC composition with RF + GH vs. RF
alone were not significant. In the deep GSTRCm, a 2x increase of
Type I MHC and approximately the same reduction in Type IIB and IIX MHC
occurred with UN into senescence. These changes were reversed with RF
and RF + GH. In the superficial GSTRCm, an effect of aging into
senescence was noted in controls with >2x increases in Types I and
IIA, and a >2x decrease in Type IIB, MHC. These changes were
strikingly reversed back to either zero or the prior control value by
UN. A trend for increased Type IIX MHC into senescence also was
suggested followed by a significant halving with UN. All of these
UN-induced changes in the superficial GSTRCm were reversed with RF
and RF + GH. Numerically, average Type IIA MHC composition of the
prototypical fast EDLm was more than doubled with UN (ANOVA
P = 0.15) (Table 2
), whereas Type IIA MHC of the
prototypical slow SOLm was one-third less (ANOVA P
= 0.18). These differences displayed a trend in the appropriate
paradoxical directions suggestive of hormonal regulation of Type IIA
MHC expression in these specific prototypical muscles
(Schiaffino and Reggani 1994
). A slightly greater sample
number in each group would likely show these differences to be
statistically significant. Finally, the mixed-MHC DIAm did show
some UN- and GH-dependent shifts, in agreement with our prior
results (Ameredes et al. 1998a
). Taken together, these
data suggest that: 1) chronic UN may drive some muscles
toward expression of certain predominant MHC isoforms, 2) RF
and RF + GH can reverse these adaptations, and 3) these
effects are pronounced in muscles with largely mixed-MHC
composition. Thus, these results are consistent with the idea that
largely mixed-MHC muscles such as the deep GSTRCm and DIAm may have
greater adaptive flexibility than those with more homogeneous MHC
composition, such as the SOLm and EDLm.
Our methods allowed quantification of the relative MHC composition of
the muscles, but not assessment of the actual amount of MHC within the
muscles. Therefore, we cannot say conclusively whether these MHC shifts
occurred due to either increases in the amounts of MHC, decreases in
the amounts of MHC, or "switching" of isoforms (Izumo et al. 1986
). For instance, in the deep GSTRCm decreased amounts of
type IIB and IIX MHC are a possibility, perhaps due to protein
catabolism that occurs with chronic food restriction (McGilvery 1979
). However, switching of MHC isoforms also is likely,
perhaps due to hormone-driven shifts toward slower MHC isoform
expression (Izumo et al. 1986
). We suggested previously
(Ameredes et al. 1998a
, and 1999
) that this will
remain unknown until reliable methods are developed to determine the
absolute amount of type-specific MHC within muscles.
Potential significance of MHC shifts.
It may be that the UN-driven increases in type I and IIA MHC
composition of the GSTRCm may be beneficial because it is
characteristic of slower muscle fibers that utilize more efficient
oxidative processes for the energy provision (Sieck 1988
). Thus, in the face of limited energy substrates, a shift
toward predominance of MHC isoforms and fibers associated with
efficient energetic processes would seem to be an advantageous
adaptation to chronic UN. This would allow efficient use of the limited
energy substrates, however it could significantly compromise the force,
velocity, and power capacity of the muscles (Ameredes et al. 1999
, Schiaffino and Reggani 1994
), making
response to a physical challenge difficult. This issue may be of
critical importance when therapy for replenishment of muscle bulk,
strength and physical capacity of the aged cachectic individual is
considered.
Possible role of GH and testosterone.
GH is considered to be one of the most important protein anabolic
agents in the body and is essential for protein synthesis throughout
life (Everitt and Meites 1989
). It has been shown to be
decreased with aging (Corpas et al. 1992
) and to reverse
catabolic states (Clemmons and Underwood 1992
).
Testosterone levels also have been shown to fall with food restriction
and aging in adult male mammals (Corpas et al. 1992
,
Howland 1975
, Lamberts et al. 1997
).
Because the anabolic actions of these hormonal factors are important in
maintenance of mammalian male muscle mass and function throughout life
(Everitt and Meites 1989
, Lamberts et al. 1997
, Proctor et al. 1998
, Wu 1997
), it would be logical that decreases might significantly
influence muscle phenotype. Consequently, it might also be expected
that GH administration would reverse some of these changes. As
indicated above, trends in MHC alterations in the SOLm and EDLm were
suggestive of a UN and subsequent GH effect. We did, however, observe
significant RF and RF + GH-driven MHC shifts, protein elevations
and mass increments in the GSTRCm concomitant with increased
circulating testosterone levels (Fig. 5
). These results are
consistent with the possibility that GH is one of the critical factors
regulating atrophy, hypertrophy and MHC shifts in the present model.
Another potentially important factor in the hormonal regulation of
muscle phenotype is insulin-like growth factor I (IGF-I). IGF-I
is the active anabolic agent derived from GH and therefore is the
critical mediator of anabolic effects typically attributed to GH
(Daughaday and Rotwein 1989
). IGF-I also is known to
produce significant hypertrophy and increased MHC content in skeletal
myofibers (Vandenburgh et al. 1991
). Similar to
testosterone, IGF-I levels also decline with aging (Corpas et al. 1992
) and UN (Lanz et al. 1992
,
Thissen et al. 1994
) and have been implicated as a
possible signal responsible for decrements in protein synthesis
capacity (Clemmons and Underwood 1992
, Richardson 1981
). Given that IGF-I was previously shown to be
decreased with chronic UN in this same rat sex and strain (Lanz et al. 1992
), and in other hypocaloric models (Thissen et al. 1994
) the changes in muscle and body mass that we
observed with chronic UN suggest a possible role for IGF-I.
Moreover, GH is a potent stimulus for IGF-I production
(Thissen et al. 1994
). Thus, an increase in circulating
IGF-I with RF + GH (Lanz et al. 1992
) could be a
likely factor promoting the reversal of UN-induced changes we
observed.
The exact nature of the interaction between testosterone, GH and
IGF-I in our experiments is unknown. Possibly, chronic UN resulted
in decreased activity of the thyroid resulting in a decrement in
IGF-I production (Keiss et al. 1993
,
McGilvery 1979
, Thissen et al. 1994
). The
levels of tri-iodothyronine with chronic UN as compared to controls
(UN = 560 vs. C = 890 ng/L) were reported elsewhere
(Ameredes et al. 1998
) and are consistent with this
possibility. Unfortunately, simple linkage of decreased thyroid hormone
production to rat skeletal and respiratory muscle MHC profile has been
nonuniform (Florini 1989
, Gosselin et al. 1996
, Izumo et al. 1986
) and possibly dependent
on the methods utilized to induce hypothyroidism. Further study is
needed to better establish the relationships between these critical
anabolic factors in long-term models of aging and undernutrition.
Conclusion and critique.
In conclusion, we found that GH in conjunction with RF resulted in
greater and more rapid increments in body mass replenishment after
chronic UN in aging rats. This effect was reflected as a trend toward
mass overshoot with GH treatment in the whole gastrocnemius muscle. We
also found that mixed-fiber type muscles such as the gastrocnemius
and the diaphragm displayed the greatest MHC shifts in response to RF
and RF + GH. These changes were associated with alterations in
circulating testosterone levels, which may be a key factor in these
processes. Although we did not measure IGF-I, the known property of
GH as a precursor for IGF-I (Daughaday and Rotwein 1989
) and data from a prior study in a similar model
(Lanz et al. 1992
) suggest that it may have played a
role as well.
It should be noted that, while the final changes observed in muscle
mass, MHC shifts, protein concentrations and testosterone at senescence
were not significantly different between the treatments of RF + GH and
RF alone. This may have been due to the design of our study. The design
ended the study with achievement of the control body mass by the group
treated with RF alone as opposed attainment of that body mass by the RF
+ GH group. The fact that the RF + GH group attained this endpoint
significantly (2.5 mo) sooner and remained greater than the RF group
suggests that muscle sampling at, or just after, 21.75 mo of age could
have resulted in significant differences in the muscle characteristics
between the treatments of RF + GH and RF alone. Moreover, this time
point also qualifies as senescence for this species (Yu et al. 1985
) and therefore indicates that GH treatment was effective
in enhancing the effects of RF into senescence. These findings suggest
that GH administration in conjunction with RF can reverse atrophy and
reestablish body mass significantly more rapidly than RF alone, and
therefore should be further considered in treatment of aged chronically
undernourished individuals.
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ACKNOWLEDGMENTS |
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|
FOOTNOTES |
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3 Abbreviations used: ADFC, average daily food consumption; DIAm, diaphragm muscle; EDLm, extensor digitorum longus
muscle; GH, growth hormone; GSTRCm, gastrocnemius muscle; IGF-I, insulin-like growth factor I; MHC, myosin heavy chain; RF, refeeding;
RF + GH, refeeding + growth hormone; SOLm, soleus muscle; UN, undernutrition.
4 Rats (F344/NH1a®CVF®; Hilltop Lab Animals,, Scottsdale, PA; delivery wt. = 200–224 g,
approximate age = 2 mo, n = 50); Purina Rat Chow [Prolab® RMH 3000, Purina, Inc., Richmond, IN;
composition (g/100 g): protein = 22.5, fat = 10.9, crude fiber = 4, ash = 6.1, nitrogen-free extract = 52,
vitamin and mineral balance = 4.5; physiological fuel value = 14.47 kJ/g, metabolizable energy value = 13.39 kJ/g).
Manuscript received May 19, 1999. Initial review completed July 26, 1999. Revision accepted September 13, 1999.
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