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Division of Pulmonary/Critical Care Medicine, Cedars-Sinai Medical Center, Burns and Allen Research Institute, University of California Los Angeles School of Medicine, Los Angeles, California 90048
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Lewis, Michael I., Thomas J. LoRusso, and Mario Fournier.
Anabolic influences of insulin-like growth factor I and/or growth hormone on the diaphragm of young rats. J. Appl. Physiol. 82(6): 1972-1978, 1997.
It is
controversial whether insulin-like growth factor I (IGF-I), growth
hormone (GH), or their combination might enhance body growth
and/or tissue anabolism in the well-fed animal with an intact
somatotrophic axis. To assess this further, we studied four groups of
adolescent rats: 1) control (Ctr),
2) GH,
3) IGF-I, and
4) GH/IGF-I. IGF-I was given via an
osmotic minipump, whereas GH was injected subcutaneously for a period of 72 h. Diaphragm (Dia) contractile and fatigue properties were determined in vitro. Quantitative histochemical and morphometric analyses were performed on Dia fibers. Total serum IGF-I levels were
significantly increased in the groups receiving growth factors. Although body weight increased to a greater extent in the animals receiving growth factors, a further synergistic effect was noted in the
GH/IGF-I animals compared with either GH or IGF-I groups. Costal Dia
mass was greater in the groups receiving growth factors. The Dia of
GH/IGF-I animals was more fatigue resistant than the Dia in Ctr. The
cross-sectional area of types IIa and IIx fibers were increased to a
similar extent in all groups receiving growth factors compared with
Ctr. Succinate dehydrogenase activity of type IIa fibers was
significantly greater in the GH/IGF-I animals compared with the other
groups. We conclude that the short-term provision of growth factors to
well-nourished, normally growing adolescent rats can accelerate body
growth and promote selective hypertrophy of predominantly type II Dia
fibers.
growth factors; diaphragm fiber cross-sectional area; succinate
dehydrogenase; diaphragm contractility and fatigue
INTRODUCTION ACUTE NUTRITIONAL DEPRIVATION causes significant
atrophy of diaphragm (Dia) muscle fibers in adolescent rats (21). We
previously reported that insulin-like growth factor I (IGF-I) but not
growth hormone (GH) diminished the reduction in cross-sectional areas (CSAs) of all Dia fibers in an adolescent rat model of acute
nutritional deprivation for 72 h (20). It is controversial, however,
whether IGF-I alone or in combination with GH can enhance body growth and/or tissue anabolism in the well-fed adolescent animal in
which the somatotrophic axis is intact. For example, Schalch and
co-workers (29) reported a 41% increase in growth rate in malnourished young rats receiving an IGF-I infusion over 7 days but no change in
growth rate in young rats fed ad libitum and given an identical regimen
of IGF-I. Similar findings were noted in a follow-up study in which
growth rate and nitrogen balance were unaffected by IGF-I infusion in
well-fed young rats (34). In contrast, Hizuka and colleagues (14)
reported significant increments in body weight gain, body length,
tibial epiphyseal width, and organ weight in young rats administered
IGF-I over a 7-day period. Similarly, Tomas et al. (33) reported a
dose-dependent increase in body weight gain, nitrogen retention, and
muscle protein synthesis in growing rats given IGF-I for 14 days.
A number of well-described influences of IGF-I may underlie the
apparent effect or lack of effect noted in some of these studies examining well-fed growing animals. For example, infusion of IGF-I reduces plasma levels of insulin and/or amino acids, thus
diminishing overall anabolism (6, 15). In addition, in animal and human studies, IGF-I infusion has been reported to reduce the concentration of circulating GH, possibly by suppressing GH release (13, 27, 28).
This may affect the direct effects and/or
paracrine influences of IGF-I on target tissues. Reduced circulating
levels of GH and insulin may alter serum levels of IGF binding proteins
(IGFBP), because GH and insulin normally inhibit IGFBP1 and GH
increases IGFBP3 (6). On the other hand, IGF-I may improve absorption and food efficiency by increasing the size of jejunal villi (27).
The aim of the present study was to evaluate the short-term effects of
IGF-I alone or in combination with GH on Dia structure and function in
a well-nourished adolescent rat model, by using a protocol similar to
the one used in our acute nutrition-deprivation study (20). We
specifically wished to address whether IGF-I or GH exerts an anabolic
effect on Dia muscle fiber morphometry, and, if so, whether the effects
of IGF-I and GH differ from each other. Furthermore, because GH may
offset some of the influences of IGF-I treatment [for example,
attenuating the decline in plasma insulin concentrations (17)],
and the changes in IGFBPs, we wanted to assess whether the combination
of GH and IGF-I exerts additive or synergistic effects.
METHODS
1 · day1
in humans vs. 3-5
mg · kg1 · day1
in animal studies, including the present study). Thus the dosage regimens were selected specifically to test whether the dosage regimens
that exhibit anabolic effects in the malnourished state (20) would
exert an anabolic effect in well-nourished animals with an intact
somatotrophic axis.
In vitro assessment of isometric contractile and fatigue properties
of the Dia.
The contractile and fatigue properties of the Dia in vitro were
determined by using methods identical to those described in detail in
our earlier studies (22, 30). Briefly, the entire Dia was rapidly
excised after the induction of deep anesthesia (pentobarbital sodium; 6 mg/100 g body wt ip). A narrow 3- to 4-mm-wide strip of Dia was cut
from the right midcostal region, maintaining fiber attachments to the
ribs and central tendon intact. The segment of Dia was vertically
mounted in a tissue bath containing Krebs-Henseleit solution that was
maintained at a temperature of 26°C and constantly aerated with
95% O2-5%
CO2. The costal margin clamp was
attached to a calibrated force transducer (Grass FT10), and the central
tendon clamp was attached to a micromanipulator (Kopf). The Dia strip
was directly stimulated by using 2-ms monophasic impulses at
supramaximal intensity (Grass S88 stimulator).
d-Tubocurare (12 µm) was added to
the tissue bath to block neuromuscular transmission. Muscle length was
adjusted until maximum twitch force responses were obtained
isometrically. Isometric contractile and fatigue properties were
studied at this optimal length
(Lo), which was measured by using a digital caliper accurate to 1 µm (Mitutoyo).
Peak twitch force (Pt),
contraction time (CT; time to
Pt) and half relaxation time
(RT1/2; time for
Pt to fall to half maximum) were
determined from a series of single pulses. Force-frequency relationships were measured for a range of stimulus frequencies from 5 to 100 pulses per second (pps). The stimuli were presented in trains of
1-s duration, with an interval of at least 30 s intervening between
each stimulus train. Pt and
maximum tetanic force (Po) were
normalized for the estimated CSA of the muscle segment (CSA = muscle
wt/1.056 × Lo, where 1.056 g/cm3 represents the density of
muscle) and expressed in newtons per square centimeter.
Fatigue resistance of the Dia muscle was determined by using a fatigue
test, whereby repetitive stimuli were presented over a 2-min period
(i.e., 40 pps in trains of 330 ms repeated each second). A fatigue
index was calculated as the ratio of the force after 2 min of
stimulation to the initial force.
Histochemical procedures: Dia fiber-type proportions and CSA.
The muscle segment used for physiological studies and an adjacent
separate strip of Dia were stretched to
Lo, mounted on
cork, and then rapidly frozen in isopentane that had been cooled to its
melting point by liquid nitrogen. The unstimulated (fresh) segment of
Dia, adjacent to the segment used for muscle stimulation in vitro, was
used for all histochemical studies. Once
Lo for the
stimulated strip was established, it was measured, and the fresh
adjacent strip was mounted on cork at that
Lo and rapidly frozen. Serial cross sections of the Dia segments were cut at 10-µm
thickness with the use of a cryostat ( model 2800E, Reichert-Jung) kept
at 
20°C.
Dia muscle fibers were classified based on difference in staining
intensity for myofibrillar adenosinetriphosphatase (mATPase) after
alkaline (pH 9.0) and acid (pH 4.3 and 4.55) preincubations (12). One
additional serial section was fixed in 2% paraformaldehyde at pH 7.4 for 2 min at room temperature and then preincubated at pH 10.4 [modification of method of Guth and Samaha (12); see also Ref.
9]. These various staining procedures allow the classification of
fibers into several types, i.e., types I, IIa, IIb, IIx, and IIc (9,
11). Proportions of fiber types were determined from a sample of
200-300 fibers from each muscle. In previous studies in both
hamsters and rats, we verified Dia muscle fiber type
immunohistochemically, with 95% or more correspondence between the
mATPase-based classification and the major isoform of myosin heavy
chain (MHC) in single Dia fibers (9).
Dia muscle fiber CSA was determined from microscopic images of
digitized muscle sections by using a computer-based imaging processing
system. The latter is composed of a Leitz Laborlux S (Leica)
microscope, charge-coupled device video camera system (model VI-470; Optronics Engineering, Goleta, CA), high resolution Trinitron color video monitor (model PVM-1343MD; Sony, Japan), 486 DX/50-MHz PC with a Targa+ imaging board (Truvision), and Mocha
image-analysis software (version 1.20, Jandel, San Rafael, CA). A microscope stage micrometer was used to calibrate the imaging system for morphometry. The CSA of individual fibers was determined from the number of pixels within outlined fiber boundaries.
Histochemical procedures: Dia fiber oxidative capacity.
The methodology employed to quantify succinate dehydrogenase (SDH)
activity of individual Dia muscle fibers has been described in detail
in previous reports (2, 3, 31, 32). Briefly, in the histochemical
reaction for SDH, the progressive reduction of nitroblue tetrazolium
(NBT) to an insoluble colored compound [a diformazan (dfz)]
is used as a reaction indicator. The reduction of NBT is mediated by
H+ released in the conversion of
succinate to fumarate. In a series of 6-µm sections, the incubation
medium contained a large quantity of succinate (60 mM); thus the SDH
reaction was not substrate limited (3). In other sections, succinate
was absent from the incubation medium so that the reduction of NBT in
these sections was nonspecific (3). These sections are referred to as
tissue blanks.
The concentration of NBT-dfz deposited within a muscle fiber was
calculated by using the Beer-Lambert equation
![[NBT-dfz] = <FR><NU>OD</NU><DE><IT>K</IT> × <IT>L</IT></DE></FR>](/content/vol82/issue6/fulltext/1972/img001.gif)
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RESULTS
significantly
different from GH or IGF-I. P value <0.05 was regarded as significant.
The weight of the costal Dia was significantly greater in all the groups receiving growth factors, compared with Ctr (Fig 1; P < 0.05). However, the Dia weights were similar between the GH, IGF-I, and GH/IGF-I groups. The ratio of costal Dia weight (mg) to body weight (g) was similar between all the groups (Ctr, 1.9 ± 0.2; GH, 2.0 ± 0.2; IGF-I, 2.0 ± 0.2; GH/IGF-I,1.9 ± 0.1). Although this similarity suggests that the increments in both body and Dia weights in the animals receiving growth factors were proportional, a confounding variable may be the response of individual tissues and organs to the growth factors, either alone or in combination. IGF-I levels. Total serum IGF-I levels were significantly increased in the groups receiving growth factors, compared with Ctr (P < 0.05; Table 1). As noted in Table 1, serum IGF-I levels in experimental groups ranged from 1.5 times Ctr level (i.e., GH group) to 2.5 times Ctr level (i.e., GH/IGF-I group).
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, Ctr;
, GH; 
, IGF-I; 
, GH/IGF-I; pps, pulses/s. Values are
means ± SD.
Histochemistry: fiber proportions and CSA. Dia fiber type proportions were similar among all the groups (Table 3). No significant differences among the groups were observed in the CSA of type I fibers (Fig. 3). However, the provision of IGF-I, GH, or the combination of IGF-I and GH resulted in a significant increment in the CSA of type IIa fibers, compared with Ctr (P < 0.05; CSA ~27-32% larger than Ctr; Fig. 3). In addition, the CSA of type IIx fibers in the IGF and GH/IGF groups were significantly greater than in Ctr animals (P < 0.05; CSA ~26% larger than Ctr; Fig. 3). There was also a tendency for type IIx fibers in the GH group to be larger than Ctr (P < 0.1; CSA ~19% larger than Ctr; Fig 3). Thus the provision of growth factors had a significant impact on type II Dia fibers.
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Histochemistry: fiber SDH activity. SDH activity was significantly greater in type IIa fibers of animals receiving the combination of GH and IGF-I compared with Ctr (P < 0.05; Fig. 4). No other differences were observed for SDH activity in the other fiber types among the various groups (Fig. 4).
DISCUSSION
This study demonstrated a significant increment in body weight in well-fed adolescent rats after short-term administration of IGF-I, GH, or the combination of IGF-I and GH, with a greater effect observed in the group receiving the two growth factors combined than either IGF-I or GH alone. Costal Dia weight was similarly increased in all groups receiving growth factors. Improved Dia fatigue resistance and increased SDH activities of type IIa fibers were observed in the GH/IGF-I group. Moreover, increased CSA of type II fibers (IIa; IIx) was found after growth factor treatment.
Body weights. Controversy exists concerning whether well-fed animals with an intact somatotrophic axis exhibit an anabolic response to growth factors (e.g., IGF-I). For example, it has been argued, in studies showing a minimal or absent somatogenic response to IGF-I (6, 29, 34), that suppression of serum insulin and amino acid levels may occur with the use of IGF-I, which may enhance proteolysis and limit substrate uptake (6, 15, 26). Furthermore, IGF-I suppresses plasma levels of GH, decreases the GH response to growth hormone-releasing factor challenge, and downregulates hepatic GH receptors (13, 27, 28). IGF-I may also modulate levels of IGFBP. For example, IGF-I infusion for 3 days resulted in increased levels of IGFBP1, an effect likely related to suppressed serum insulin levels (6, 19). IGFBP1 has the potential to inhibit the action of administered IGF-I (16). In the present study, a positive impact on body weight was noted with the administration of growth factors, with greatest effect observed after administering the combination of GH and IGF-I. In keeping with our findings, recent studies both in animals (24) and in humans (17), with imposition of modest caloric restriction, reported that the addition of GH to IGF-I was significantly more anabolic than either agent alone. Possible mechanisms for this observation include blunting the decline in serum insulin levels induced by IGF-I, with the coadministration of GH, and increasing the serum levels of IGFBP-3 and its acid-labile subunit (ALS). Both IGFBP3 and ALS are GH responsive and could promote a more stable pool of circulating IGF-I (35). In addition, GH itself could promote protein synthesis (25) systemically or locally by enhancing autocrine/paracrine effects on target extrahepatic tissues. IGF-I, on the other hand, may also improve the absorptive capacity of the jejunum, by increasing the size of jejunal villi and crypts (5), and increase protein synthesis (10, 15), thus contributing to positive protein turnover in this model. It is not entirely clear why some studies (14, 33), including the present study, demonstrated a positive anabolic impact on body weight after growth factor administration, whereas other studies did not (6, 27, 29, 34). Differences in species, age, gender, size, and growth profile of the animals tested, as well as the duration of administration, may explain some of the variances. In rat studies, the dose of IGF-I also varied with regard to both daily dose (120-278 µg/day sc by infusion) and total dose administered (600-3,892 µg). No clear trend could be discerned among the variables listed above. In studies in rats, positive responses were noted in young growing animals (14), and a dose response was noted in female rats (33), but strong inferences regarding these observations cannot be made. Dia morphometry and biochemistry. In the present study, a significant increment in the size of type IIa Dia fibers was observed after IGF-I, GH, or the combination IGF-I and GH treatment, with a similar impact on type IIx Dia fibers in the IGF-I and GH/IGF-I animals, whereas no effect was noted in type I fibers. The mechanisms underlying this selective effect are not presently known. Whether differences exist in receptor density, sensitivity to ligand binding, or levels of IGFBP within muscle fibers [e.g., IGFBP4, which may modulate the effects of IGF-I within muscle fibers (16, 35)] is speculative and needs to be explored further. It is of interest, however, that Lanz and co-workers (18) also reported an apparent preferential effect of GH on Dia myofibers containing fast MHC isoforms in a refeeding model in the adult rat. In their study, after a period of malnutrition, the CSA of Dia fibers containing MHC 2B and MHC 2X isoforms were still reduced compared with Ctr animals, despite either 5 or 9 wk of refeeding (18). The provision of GH, in addition to food ad libitum, for 5 wk resulted in a return of the fast fiber CSA to Ctr values (18). Despite our finding of a significant effect of either GH or IGF-I alone on both costal Dia weight and type II Dia muscle fiber CSA, we did not observe a synergistic impact on either Dia weight or Dia muscle CSA with the combination of GH and IGF-I, as was observed with the change in body weight over the experimental period in the GH/IGF-I animals. As body weight encompasses both carcass and organ weights, it is possible that a greater effect was observed in some organs with the combination of GH and IGF-I than with either agent alone. This may be accounted for in part by the fact that both IGF-I and GH exhibit some degree of organ selectivity, for example, greater splenic sensitivity with IGF-I (6). It is unclear, however, why a synergistic effect was not observed in the Dia of GH/IGF-I animals. Perhaps dosage regimens producing higher serum IGF-I levels or a longer duration of administration would have yielded a greater effect with the combination of growth factors. Biochemically, however, improved oxidative capacity of type IIa Dia fibers was observed in the GH/IGF-I animals but not in the animals receiving GH or IGF-I alone. Dia contractile and fatigue properties. The use of GH, IGF-I, or the combination of GH and IGF-I had no impact on Lo, twitch characteristics, specific force, or force-frequency relationships of the Dia. The preservation of specific force can in part be explained by no alteration in the estimated relative contribution of the various fiber types to total costal Dia area in the groups receiving growth factors, compared with the Ctr animals. However, because of a greater myofibrillar mass with preserved specific force, the total force-generating capacity of the costal Dia would be expected to increase in the animals receiving growth factors. Dia fatigue resistance was improved in the group receiving the combination of GH and IGF-I. This may in part be related to the increase in SDH activity in type IIa Dia fibers. Although a significant correlation exists between fatigue resistance and SDH activity in motor unit studies (8), the contribution of SDH activity to fatigue resistance in whole muscle preparations cannot be quantified, as a variety of factors may interact to influence muscle fatigability. These include alterations in the relative contribution of various fiber types to total muscle CSA, reduced creatine phosphate, changes in calcium flux, mATPase activity, capillarity, substrate and electrolyte content, and alterations in redox state. The improved Dia fatigue resistance, together with the likely increment in the total Dia force-generating capacity in the GH/IGF-I animals, would be expected to enhance the endurance capacity of the Dia. In summary, these studies demonstrate that GH and IGF-I may exhibit an anabolic effect in well-nourished adolescent rats. A synergistic effect on body weight gain was observed with the combination of GH and IGF-I compared with the administration of either agent alone. GH, IGF-I, or the combination of GH and IGF-I had a positive but similar impact on both Dia weight and the CSA of predominantly type II Dia fibers (IIa; IIx). No synergistic effect was noted with the combined use of GH and IGF-I, apart from higher SDH activity in type IIa fibers. Although the results of this study are somewhat provocative, the potential implications for use of these growth factors, either alone or in combination, in conditions of short stature or growth retardation secondary to chronic disease in children will require further investigation in both animal and human studies (4).ACKNOWLEDGEMENTS
The authors gratefully acknowledge the encouragement and advice of Drs. Shlomo Melmed and Ross Clark and the secretarial assistance of Darlene Ford.
FOOTNOTES
Address for reprint requests: M. I. Lewis, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Rm. 6732, Los Angeles, CA 90048 (E-mail: LEWISM{at}CSMC.EDU).
Received 9 October 1996; accepted in final form 19 February 1997.
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