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Regional distribution of fiber types in developing baboon diaphragm muscles.

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THE ANATOMICAL RECORD 224~66-78(1989)
Regional Distribution of Fiber Types in
Developing Baboon Diaphragm Muscles
LEO C. MAXWELL, THOMAS J . KUEHL, ROGER J.M. McCARTER, AND
JAMES L. ROBOTHAM
Departments of Physiology (L.C.M., R.J.M.M.), Pediatrics, and Anesthesiology (J.L.R.),
The University of Texas Health Science Center at San Antonio, and Southwest Foundation
for Biomedical Research (T.J.K.), San Antonio, Texas 78284
ABSTRACT
Fiber type distribution and mean fiber area were determined for
seven sites in diaphragm muscles of premature (140 days gestation), full-term (180
days gestation), and adult baboons. Within a group, data did not differ significantly amongst the seven sites. The diaphragm of premature animals had a large
proportion [56(f2)%] of type IIc fibers, smaller proportions of type I, 110,and IIh
fibers [16(*2), 21(+1), and 7(f2)%, respectively], and no type IIg fibers. Full-term
animals had fewer type IIc [2(*1)%] fibers, greater proportions of type I [46(+2)%],
IIh [23(f1)%],and IIg [11(+ 1)%]fibers, and a similar proportion of type 110 fibers
[17(+1)%]. Diaphragm from adult baboons had similar proportions of type I, 110,
IIh, IIg, and IIc fibers in females [39(&4),20(*2), 1(*1), 41(*5), and 1(*1)%] and
males [48(*2), 16(*1), O(*O), 36(+2), and 3(*2)%1. Fiber area for premature
[143(f9), 210(+15), 231(*15), and 156(f16) pm2 for type I, 110,IIh, and IIc fibers],
newborn [317(*32), 374(+36), 468(*42), 498(&43),and 322(*37) pm2 for type I,
110,IIh, IIg, and IIc fibers], and for type I, 110,IIg, and IIc fibers from adult female
[1,759(*130), 2,365(*284), 5,026(+742), and 1,843(*111) pm2] and adult male
[2,513(+221),3,987(*267), 6,102(*376), and 2,833(*151) pm21baboons indicated
growth which correlated with body weight. Our results also show that metabolic
and contractile enzymes develop normally, but growth of respiratory muscle fibers
is arrested, during 10 days following premature birth.
No age group has as high an incidence of respiratory
failure as premature human infants. In view of this,
considerable attention has been given t o the biochemical, morphological, and mechanical development of
the lungs and chest wall (Hallman and Gluck, 1977;
Hodson, 1977). In neonates and infants, the highly
compliant rib cage and the pathologies associated with
hyaline membrane disease, aspiration syndromes, and
bronchopulmonary dysplasia all place great loads on
the muscles of respiration (Bryan et al., 1977). The role
which fatigue of the respiratory muscles can play in the
clinical expression of pulmonary disease has gained increasing recognition (Derenne et al., 1978ax). Nevertheless, there remain few studies on the contribution
which prenatal respiratory muscle development makes
to the respiratory capabilities of premature and term
human (Farkus-Bargeton et al., 1977; Keens et al.,
1978; Keens and Ianuzzo, 1979; Maxwell et al., 1984) or
animal (Maxwell et al., 1983, 1984) infants.
We have studied the respiratory muscles of a nonhuman primate (Papio cynocephalus) from late gestation
through adulthood. Premature baboon infants develop
a disease which is indistinguishable from human respiratory distress syndrome (Coalson et al., 1982; Escobedo et al., 1982). Using this model, we have previously reported histochemical data on selected sites of
costal diaphragm and intercostal muscles, and fatigability studies of diaphragm muscle bundles (Maxwell et
al., 1983). In agreement with the studies of human in0
1989 ALAN R. LISS, INC.
fants (Keens et al., 1978; Keens and Ianuzzo, 19791, we
observed a progressive increase in the proportion of
type I fibers beginning during the third trimester of
gestation and continuing into postnatal life. This increase was a t the expense of immature type IIc fibers
and suggested transformation of contractile characteristics during gestation. We found no fibers in premature baboons which exhibited the low oxidative capacity of adult type IIg (type 11, glycolytic) fibers.
Furthermore, the muscles of premature baboons were
more resistant in vitro to tests of isometric fatigue than
the muscles of adults. We therefore concluded that the
muscles of premature baboons were not predisposed to
fatigue by their intrinsic capabilities. This was in
marked contrast t o the conclusions of others on developing human muscles, which were interpreted as being
highly fatigable due to low oxidative capacity (Keens et
al., 1978; Keens and Ianuzzo, 1979). Possible reasons
for this difference include 1) species difference; 2) the
use of delayed autopsy samples; 3) variable time of respiratory function; and 4) regional differences in diaphragm characteristics amongst the sample sites chosen for study. We have presented evidence (Maxwell et
al., 1984) that muscle fibers of human infant dia-
Received June 8, 1988; accepted October 17, 1988.
FIBER TYPES IN BABOON DIAPHRAGM
phragms have a high oxidative capacity and an appearance very similar to the baboon muscles if obtained
shortly after death. However, delay of more than a few
hours between death and sampling adversely affected
the histochemical demonstration of oxidative enzymes.
Thus, the first possibility is eliminated and the second
possibility does contribute to the difference in results.
The purpose of the current study was to address the
third and fourth possibilities.
In our previous studies, premature baboons were
delivered by hysterotomy and sacrificed immediately
(Maxwell et al., 1983, 1984). The current study differs
since we studied diaphragm muscles of prematurely
delivered baboons maintained by intensive neonatal
care for 1-11 days after birth. Although some respiratory movements by fetal baboons can be detected in
utero (unpublished observation), the pattern of respiration and the level of respiratory effort change drastically at birth. Therefore, it was necessary to study the
development of respiratory muscles of prematurely delivered baboons during the first 2 weeks of extrauterine life in order to detect differences in development of
respiratory muscle fibers subjected to the additional
work load of breathing. In the current report, we compare and contrast the extrauterine development of
diaphragm muscle fibers to the development of diaphragm muscle fibers in utero a t the same postconceptional age. We examined samples from seven standardized sites of the diaphragm muscles of premature, term,
and adult baboons to detect any regional differences in
the fiber-type proportions during pre- and postnatal
development of males and females.
MATERIALS AND METHODS
Premature baboons were delivered by hysterotomy
a t 140'3 days of gestation and maintained by neonatal
intensive care procedures. Beginning at birth, all animals received intravenous (IV) fluids containing 5%
glucose. After 48 hours, the IV fluid was changed to
one containing vitamins, trace elements, amino acids,
and an increasing concentration of glucose. For 24-48
hours after delivery, all animals were paralyzed with
pancuronium bromide (initial dose 0.2 mglkg IV; supplemental intramuscular [IM] doses as required every
8-12 hours) and received either high-frequency oscillatory ventilation (HFOV) or positive pressure ventilation (PPV). Beginning on the third day, pancuronium
administration was discontinued and ventilation was
provided as required to maintain P,Oz a t 65k15 torr
and P,C02 at 40&10 tom. Most animals breathed spontaneously during some time intervals, and some were
able to be extubated for most of their subsequent extrauterine life. The details of ventilation are given in
Table 1. Body weight was determined daily, and data
are in Table 2. At 1, 4, or 11 days after delivery, the
animals were sacrificed by exsanguination following
intravenous administration of ketamine (10 mg/kg)
and Valium (0.5 mg/kg). Samples were removed from
seven standardized sites of diaphragm muscles (Fig. 1).
For the study of regional distribution of fiber types
during development, diaphragm muscles were obtained from six premature (delivered by hysterotomy
at 14023 days gestation and sacrificed at 4-6 days
after delivery), ten term (vaginal delivery at 18227
days gestation, sacrificed a t 1-9 days after birth), and
67
TABLE 1. Ventilatory status of prematurely
delivered baboons'
Ventilatory status
0 day group (N = 5)
X4577
Not ventilated; sacrificed at delivery
X4578
Not ventilated; sacrificed at delivery
R 84
Not ventilated; sacrificed a t delivery
AJ 83
Ventilated three hours while paralyzed
UB 83
Ventilated three hours while paralyzed
1 day group (N = 3), all paralyzed
0 83
PPV while paralyzed
P 83
PPV while paralyzed
P 84
PPV while paralyzed
4 to 6 day group (N = 61, all paralyzed days 1 and 2
E 83
HFOV; spontaneous breathing beginning on
day 3
F 83
PPV; spontaneous breathing beginning on
day 3
H 83
PPV; spontaneous breathing beginning on
day 3
I83
HFOV; spontaneous breathing beginning on
day 3
J 83
HFOV; spontaneous breathing beginning on
day 3
L 83
HFOV; spontaneous breathing beginning on
day 3
11 day group (N= 51, all paralyzed days 1 and 2
PPV; occasionally extubated after day 3;
Q 83
spontaneous breathing
S 83
HFOV; mostly extubated after day 3;
spontaneous breathing
PPV; mostly extubated after day 4;
V 83
spontaneous breathing
B 84
HFOV; not extubated; spontaneous
breathing
D 84
HFOV; not extubated; spontaneous
breathing
'PPV = positive pressure ventilation; HFOV = high-frequency oscillatory Ventilation.
13 adult baboons. Of these, the animals were approximately equally distributed between sexes. Seven standardized sample sites were selected. Sampling sites 1
and 2 were unavailable in most premature baboons due
to other experimental procedures.
In some baboons, additional diaphragm muscle samples were excised, blotted to remove excess surface water, and weighed. The samples were placed in a vacuum
oven overnight a t a temperature of 90°C and were
dried to constant weight. The ratio of dry to wet muscle
weight was calculated.
Muscles sampled for histochemical analysis were attached to wooden splints and frozen immediately in
isopentane cooled to its freezing point in liquid nitrogen. The frozen samples were packed in dry ice and
transported to the histochemistry laboratory. Frozen
samples were brought t o a temperature of -20°C and
10 pm cross sections were cut in a cryostat. Sections
were dried at room temperature for 30-60 min and
then incubated in a battery of histochemical media.
Reactions were performed to demonstrate the activities
of reduced nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR)and myofibrillar ATPase
activities. The NADH-TR assay was performed according to the method of Dubowitz and Brooke (1973). Myofibrillar ATPase assays were performed as described
68
L.C. MAXWELL ET AL.
TABLE 2. Body weight (grams) of prematurely delivered baboons’
Day
ID No.
0
1
AJ 83
UB 83
X 4571
4578
R 84
0 83
P 83
P 84
E 83
F 83
H 83
I83
J 83
L 83
Q 83
S 83
Y 83
B 84
D 84
585
536
420
474
584
513
635
549
527
517
646
611
515
587
481
530
611
497
545
510
675
635
625
525
680
644
530
567
495
534
644
469
567
=
2
3
4
5
6
7
8
9
10
11
650
523
705
621
540
630
528
623
489
670
555
539
563
528
473
606
540
565
518
445
565
510
424
541
434
492
530
550
511
460
453
541
47 1
476
500
448
540
458
494
465
463
435
470
483
441
435
545
480
483
455
458
445
462
524
460
483
437
449
500
420
474
682
525
613
478
5 14
no data available.
D I A P H R A G M S A M P L I N G SITES
(Pleural S u r f a c e )
Sternum
Fig. 1. The diaphragm muscles were divided into seven regions from which samples were routinely
taken. The sites are numbered as viewed from the pleural surface. Even-numbered samples were from
the right diaphragm; odd-numbered samples were from the left diaphragm or substernal region.
by Chayen et al. (1972). Serial sections were preincubated at an alkaline pH (10.3) or a t an acid pH (4.3)
(Brooke and Kaiser, 1970; Dubowitz and Brooke, 1973)
prior to the myofibrillar ATPase assay.
Sections were observed with a Zeiss Universal I1 microscope equipped with a Panasonic video camera and
a drawing tube which allowed an image drawn on a
tracing tablet to be superimposed on the microscopic
image. The outlines of 100-200 muscle fibers from the
midportion of each sample were drawn from sections
incubated for myofibrillar ATPase after alkaline preincubation. Fibers were classified as type I or I1 based
on a low or high intensity, respectively, of the myofibrillar ATPase reaction after alkaline preincubation.
Then serial sections were viewed and the image of the
sampled fibers was superimposed on the sample drawing.
We have adopted a subclassification of those type I1
fibers which show acid reversal on the basis of NADHTR activity, while the variable proportion of type I1
fibers which did not demonstrate acid reversal were
classified type IIc. Type I1 fibers that did demonstrate
“acid reversal” following preincubation at pH 4.3, and
that had high NADH-TR activity, were called type 110
69
FIBER TYPES IN BABOON DIAPHRAGM
(type I1 oxidative) while those with low NADH-TR activity were designated type IIg (type I1 glycolytic). A
similar approach has been used previously for masticatory muscle fibers of rhesus monkeys (Maxwell et al.,
19811, regenerating fibers in muscle autografts in cats
(Maxwell, 19841, and developing fibers in baboon diaphragm (Maxwell et al., 1983, 1984). In our previous
papers, type I1 fibers high in NADH-TR activity were
called type IIa and type I1 fibers low in NADH-TR activity were called type IIb. The problem is that some
type IIa and IIb fibers classified by using NADH-TR
activity might not have been classified as type IIa and
IIb fibers by the myosin-based scheme of Brooke and
Kaiser (1970). The type IIa and IIb fibers of our previous studies are directly comparable to the 110 and IIg
fibers in our current study.
Our classification scheme is actually a combination
of the metabolic profile classification according to Peter
et al. (1972) and the myosin-based scheme of Brooke
and Kaiser (1970). The classification according to Peter
et al. (1972) is based on the demonstration of myofibrillar ATPase after alkaline preincubation and the demonstration of oxidative enzyme activity. Type I, 110, and
IIg fibers are essentially comparable to the slow-twitch
oxidative (SO), fast-twitch oxidative-glycolytic (FOG),
and fast-twitch glycolytic (FG) fibers identified by Peter et al. (1972) or to the fibers of slow-twitch (S),fasttwitch fatigue-resistant (FR), or fast-twitch fatigable
(FF) motor units classified by Burke et al. (19711, but
neither of these previous classifications identified type
IIc fibers. The classification scheme of Brooke and Kaiser, based on the characteristics of myofibrillar ATPase
after preincubation in differing pH solutions, does
identify type IIc fibers but makes no assessment of oxidative enzyme activity. Although either the Brooke
and Kaiser or the Peter et al. scheme can yield adequate data on adult muscles, we have not been satisfied
with strict adherence to either scheme for developing
or regenerating muscles. The current nomenclature is
a compromise which avoids ambiguity while combining
the desirable features of several previous classification
schemes.
We have taken care to ensure that tissue preparation, section thickness, and incubation procedures were
the same for each muscle studied. Whenever possible,
samples of fetal and adult muscles were incubated simultaneously, and we also incubated a sample of a
limb skeletal muscle. These procedures enable us to
control the quality of incubations and make comparisons of reaction intensity in different fibers within a
muscle or among muscles. Our classification criteria
for oxidative enzyme activity include overall reaction
intensity, the size of diformazan granules, and the completeness of the interfibrillar network of activity. Type
110 fibers rank higher than type IIg fibers in each of
these criteria. All type I fibers demonstrated acid reversal, and all type IIc fibers had high NADH-TR activity.
We have also done a systematic study of a kind of
fiber we observed in premature and term muscles, but
which was essentially absent from adult muscles. The
fiber is characterized by a central region containing a
relatively high NADH-TR activity, surrounded by a
peripheral zone of very low NADH-TR activity. This
gives the fibers an appearance which has led others to
call them “halo fibers” (Farkus-Bargeton et al., 1977).
We have classified such fibers type IIh in this study.
At least three microscopic fields were randomly selected from the midportion of each cross section of diaphragm. Data from these three fields were pooled for
analysis. We selected the midportion of cross sections
in order to avoid possible differences in the proportions
of fiber types on pleural and abdominal surfaces, as has
been reported for cat diaphragm (Sieck et al., 1983) and
for some regions of rat diaphragm (Metzger et al.,
1985). The cross sectional area of each fiber was determined by digital image analysis by using a Bioquant
(R&MBiometrics). Mean fiber area and the numbers of
fibers of each type in the sample were determined.
From these data, the proportion of sampled fibers and
the proportion of sample area represented by each type
of fiber were calculated. A detailed description of these
techniques has been published elsewhere (Maxwell et
al., 1983, 1984; Maxwell, 1984).
Our new data on diaphragm muscles of premature
baboons and of full-term baboons after normal birth
and our previously published data (Maxwell et al.,
1983) were used for comparison of extrauterine development of diaphragm muscles following premature delivery to the age-matched intrauterine development of
diaphragm muscle. For this analysis, we used data only
from costal sample sites, since that was the basis for
our previous published data, and we combined type IIh
fibers with the type IIa fibers of which they are a subset.
Mean, standard deviation, and standard error of the
mean were calculated on pooled data from each sample
site, for each age group, and for each sex. Unless otherwise stated, data are presented as mean ? standard
error of the mean. Data were also subjected to an analysis of variance (ANOVA), and when significance was
indicated, the groups responsible for the significance
were identified by using a Student Neumann Kuels
(SNK) test. Significance was accepted a t P<.05. All
statistical calculations were performed as described by
Zar (1974).
RESULTS
Data for the sample sites of diaphragm muscles from
baboons of premature, term, or adult age are presented
in Tables 3 and 4. In diaphragm muscles of premature
or term animals, no significant sex-related differences
in the proportion of fiber types or in the mean fiber
area were found by ANOVA. For adult baboons, however, ANOVA showed a significant difference between
males and females in the cross-sectional area of fibers,
with no difference in the proportion of fiber types.
Therefore, premature, term, adult female, and adult
male groups were studied in order t o assess differences
amongst sample sites within the diaphragm. Within
each of these groups, the proportion of fiber types
amongst different sample sites of diaphragm muscles
did not differ significantly by ANOVA (Table 3). Nor
were there significant differences (ANOVA) within
each group, amongst sample sites of diaphragm muscles, in the mean cross-sectional area of the different
types of fibers (Table 4) or in the muscle mean fiber
area (Fig. 2). Therefore, t o simplify further analysis,
the data obtained for the sites within each diaphragm
muscle were pooled, and the percentage of fibers and a
70
L.C. MAXWELL ET AL.
TABLE 3. Proportion of fiber t es for Sam le sites of premature, term, and adult diaphragm muscles
(data are mean f SE!%; three to fPve samples for each site are represented except
for sites 1 and 2 of premature diaphragm)
%
I
Site
I10
Premature (140 days gestation; 4-6 days extrauterine life)
1
2
13.95 f 3.96
3
7.61 k 2.54
22.14 f 1.86
4
5.23 k 2.49
5
5.94 k 2.99
23.98 k 3.40
30.79 f 3.39
6
7.25 4 1.89
24.59 f 0.57
7
4.85 4 2.54
Term (180 days gestation; 1-9 days postnatal life)
1
48.44 4 2.53
17.47 k 1.75
2
50.88 4 3.67
16.23 f 3.05
15.68 k 1.16
3
50.45 4 2.39
18.20 4 0.87
4
42.72 f 2.32
17.62 2 1.36
5
41.44 f 2.20
16.78 f 1.65
6
44.71 3.54
7
43.82 f 4.10
19.33 k 5.73
Adult female
1
46.70 3.80
16.57 2.17
21.19 2 2.32
2
37.90 f 4.91
14.00 1.23
45.64 4 3.26
3
20.58 4 4.74
4
39.70 4 1.87
20.33 f 2.44
41.46 2.53
5
22.15 k 3.73
38.87 4.01
6
20.98 4 2.61
36.34 f 2.51
7
Adult male
18.87 k 1.67
43.62 4 2.42
1
15.83 f 2.31
2
50.59 4 2.29
11.67 1.23
56.98 3.62
3
20.65 2.55
4
47.07 2 2.68
42.97 f 2.19
19.10 4 1.61
5
15.06 f 2.66
44.47 k 4.22
6
7
44.69 f 3.95
15.48 2 1.79
*
*
*
*
*
*
*
*
weighted mean fiber area were calculated for each fiber
type. These pooled data were taken as representative of
the histochemical profile and cross-sectional area of the
fibers in that muscle.
The proportions of fiber types and mean fiber area for
diaphragm muscles of premature, term, adult female,
and adult male baboons are plotted in Figures 3 and 4.
The diaphragm muscles of premature animals were
characterized by a large proportion [56(+2)%] of type
IIc fibers, smaller proportions of type I, 110, and IIh
fibers [16(&2),21(*1), and 7(*2)%, respectively], and
no type IIg fibers. Mean fiber area was small, having
mean values of 143(*9), 210(%15), 231(*15), and
156(*16) pm2 for type I, 110,IIh, and IIc fibers. Compared to premature baboons, the diaphragm muscles of
term animals delivered after 180 days gestation had
few [2( 1)%1 type IIc fibers, greater proportions of type
I [46(-+2)%1,IIh [23(*1)%1, and IIg [11(21)%]
fibers,
and about the same proportion of type 110 fibers
[17(21)%1. The fibers had increased in fiber area t o
mean values of 317(232), 374(+36), 468(+-42),
498(*43), and 322(*37) pm2 for type I, 110,IIh, IIg, and
IIc fibers.
Adult baboon diaphragm muscles had similar proportions of fiber types regardless of sex, having 39( +4),
20(*2), 1(*1),41(+5), and 1(*1)%of type I, 110, IIh,
*
IIh
Ik
IIC
4.63 4 1.25
4.49 4 0.74
8.93 4 2.45
5.41 f 0.75
8.07 t 1.26
0.00 k 0.00
0.00 f 0.00
0.00 k 0.00
0.00 k 0.00
0.00 k 0.00
63.81 t 3.44
58.14 4 2.45
51.13 2 3.09
46.52 5.32
52.48 f 3.46
23.19 f 1.86
21.24 t 2.76
19.29 f 1.62
23.69 4 2.12
25.62 f 1.90
23.55 f 2.02
24.14 f 2.08
7.25 4 0.95
9.78 2 1.24
11.85 k 1.23
13.19 4 1.32
12.67 f 1.98
12.87 4 1.58
11.66 4 1.28
3.57 1.12
1.87 f 0.66
2.71 4 0.64
2.15 f 0.93
2.64 4 0.70
2.08 f 0.74
1.04 k 0.48
0.00 f 0.00
0.00 f 0.00
0.00 f 0.00
0.00 k 0.00
0.00 f 0.00
0.00 4 0.00
0.00 f 0.00
36.04 f 4.90
40.74 f 5.96
39.82 3.90
39.56 4.01
37.52 k 2.92
38.74 4 3.44
42.46 4 2.72
*
0.67 2 0.45
0.00 4 0.00
0.45 t 0.45
0.17 0.17
0.35 2 0.35
0.21 f 0.21
0.20 t 0.20
0.00 f 0.00
0.00 f 0.00
0.00 4 0.00
0.00 f 0.00
0.00 2 0.00
0.00 f 0.00
36.76 f 1.11
33.23 f 1.84
31.35 4 4.10
32.07 f 2.94
37.70 k 1.80
40.46 f 3.03
39.63 f 2.54
0.59 f 0.39
0.33 f 0.33
0.00 0.00
0.19 f 0.19
0.21 f 0.21
0.00 t 0.00
0.17 t 0.17
0.00
f 0.00
*
*
*
*
IIg, and IIc fibers in females and 48(+2), 16(*1), O(+-O),
36(+2), and 3(+2)%of type I, 110,IIh, IIg, and IIc fibers
in males. Muscle fiber area in diaphragm muscles from
adult females was smaller than for the muscles from
adult males. Fiber area in muscles of females was
1,759(* 1301, 2,365(*284), 5,026(*742), and 1,843
(*111) pm2 and in muscles of males was 2,513(+221),
3,987(2267), 6,102(*376), and 2,833(+151) pm2 for
type I, 110,IIg, and IIc fibers, respectively. The difference in mean fiber area amongst premature, term,
adult female, and adult male baboons correlated very
well with body weight (Fig. 5), which averaged 5 2 , .92,
15.66, and 23.84 kg, respectively, in these groups.
Figure 6 shows the changes in fiber-type proportions
during the third trimester and the first 9 days (solid
symbols) of postnatal life after term birth. The data for
120, 138, and 163 days of gestation and for 1,5, and 8
days after term birth are pooled from current results
and from our previous report (Maxwell et al., 1983) and
plotted as a function of postconceptional age. Since we
did not classify the transitional type IIh (“halo”)fibers
in our earlier paper on intrauterine development
(Farkus-Bargeton et al., 19771, we combined the IIh
fibers into the type 110fiber pool, of which the IIh fibers
are a subset, for the current analysis. Our earlier data
for diaphragm muscle were obtained from a standard-
FIBER TYPES IN BABOON DIAPHRAGM
71
TABLE 4. Mean fiber area (MFA) for each type of fiber of sample sites in premature, term, and adult diaphragm
muscles (data are mean -C SEM)
MFA
Ik
Site
I
I10
IIh
Premature (140 days gestation; 4-6 days extrauterine life)
1
2
3
4
5
6
7
165 t 2 1
130 t 14
147 f 7
128 f 4
131 f 10
233 t 19
207 f 13
207 f 29
177 f 17
201 f 9
238
215
235
217
219
t 22
t 14
t 31
f 22
f7
IIC
MFA
165 f 14
137 f 11
160 I 2 8
121 f 9
130 f 9
177 f 14
156 2 11
174 2 25
144 t 11
154 f 8
247 f 21
313 t 50
348 f 60
311 f 55
282 f 36
407 f 122
274 f 58
347 t 33
366 f 50
395 f 48
363 t 31
360 t 22
431 f 69
389 t 4
Term (180 days gestation; 1-9 days postnatal life)
1
2
3
4
5
6
7
278
299
328
316
303
366
324
Adult female
1
1,898
2
3
4
5
6
7
f 30
f 39
f 41
f 27
f 24
f 66
f 37
445
470
486
419
428
506
474
f 39
t 56
f 62
f 36
t 20
t 82
t 42
f 212
2 113
f 119
3,020
2,520
1,840
2,176
2,096
2,017
1,994
2,329 f 289
2,731 f 382
2,208 f 208
2,113 f 172
2,411 t 122
2,583 t 265
2.442 f 117
4,464
4,566
4,015
3,370
3,794
3,608
3.723
t 715
t 773
t 260
1
2
1,817
1,332
1,583
1,535
1,533
1,579
f
132
366
383
412
348
338
414
355
t 161
t 121
f 124
f 53
t 44
482
507
516
453
474
557
513
f 68
f 55
f 39
f 23
f 76
t 58
t 432
f 143
f 92
t 163
2 175
f 215
f 50
f 83
f 57
f 39
f 26
t 70
f 59
7,069 f 367
5,070 f 808
3,577 4 257
4,206 f 328
3,931 2 217
3,828 2 208
3,900 f 385
2,170 f 50
6,865 f 851
7,295 t 1,168
6,861 f 470
5,184 f 669
6,081 2 710
5,580 f 370
5.955 2 714
2,736 f 508
2,128
1,560
1,840
1,489 t 186
1,678
1,645
3,923 t 345
3,222 t 485
2,256 f 102
2,733 f 205
2,526 f 93
2,542 f 280
2,658 f 280
Adult male
1
2
3
4
5
6
7
209
f 269
f 192
f 375
2
3
4
5
6
1,944
3,982
3.500
4,418 2 580
4,546 2 696
3,792 202
3,344 f 189
4,040 t 307
3,936 f 263
3.946 f 196
*
7
Site Number
Fig. 2. The mean fiber area for the sample sites of diaphragm muscles is shown for each group.
ized location comparable to site 4 in the current study.
Significant increases in the proportions of type I and
type 110fibers and a decrease in the proportion of type
IIc fibers occurred during the final trimester of gestation. There were no type IIg fibers observed through
163 days of gestation. Following term birth, the proportion of type I fibers stabilized near adult values, and
the proportion of type 110 fibers declined as type IIg
fibers began to appear.
The composition of the diaphragm muscle also
L.C. MAXWELL ET AL.
72
Prom
Torm
Adult Fomak Adult Male
Fig. 3. The percentage of each fiber type is shown for the diaphragm muscles of premature (140 days
gestation; 4-6 days extrauterine life), term (180 days gestation; 1-9 days postnatal life), adult female,
and adult male baboons.
a
rri
a
4
a
W
m
LL
?I
a
Prom
Trm
Adult Fomak
Adult Malo
Fig. 4. The mean fiber area from data pooled for the seven sample
sites is shown for each group. Groups are as described for Figure 3.
130212pm2, 283'33 to 209*17pm2, and 188a24 to
141k14pm2 for types I, 110,and IIc, respectively (Fig.
7). This represents a reduction of fiber area for prematurely delivered baboons to 51,63, and 63% for types I,
110,and IIc fibers, respectively, of the values for diaphragm muscle fibers of baboons after intrauterine development alone. Mean fiber cross-sectional area
(MFCSA) (Fig. 8) also declined during 11 days following premature birth from 217226 pm to 165215 pm2,
reaching 65% of the value for diaphragm muscles at
140 days of gestation.
The dry:wet weight ratios of muscle samples obtained from premature (140 days gestation) and fullterm baboons were 0.2120.01 (n=5) and 0.2520.01
(n = 7), respectively. At 4 and 11 days of extrauterine
life following premature delivery at 140 days of gestation, ratios were 0.21*0.01 (n=9) and 0.24k0.01
(n = 4), respectively. At 6-9 days following full-term
delivery, dry:wet ratio was 0.22+0.00 (n = 8).
DISCUSSION
Following premature delivery, all animals were parchanged during 11 days following premature delivery
(Fig. 6, open symbols). The proportions of type I and alyzed for 2 days, but they performed some spontanetype 110 fibers increased from 6.5'1.31 to 13.8+2.1% ous breathing episodes thereafter. Most breathed sponand from 27.521.8 to 36.8+1.7%, respectively, while taneously for a substantial portion of time after the
the proportion of type IIc fibers decreased from third postnatal day, and some long-term animals were
66.222.6 to 49.0*2.9%, and there were no type IIg fi- extubated during the last week of the study. Infants
bers. These proportions of fiber types during extrauter- gained weight during the paralysis but then lost
ine development after premature birth are in agree- weight as spontaneous respirations were initiated and
ment with values predicted by extrapolation from the pulmonary status improved. Body weights were maintained after day 3. Fluid gain during paralysis may
data for intrauterine development.
The mean fiber area increased throughout the final result since muscle movements were only passive,
trimester of gestation for type 110 and type IIc fibers, eliminating muscle activity as a means of eliminating
but only during the last month for type I fibers (Fig. 7). extravascular water from muscular tissue at a time
The growth of each of these fiber types and of the ap- when fluid support is intensive. The early fluid gain
pearing type IIg fibers continued for several days after may be related to the effects of ventilation on the carfull-term birth. However, the growth appears not to be diopulmonary function of a premature animal with
sustained, as decreases in mean fiber area were seen patent ductus arteriosus. At the end of paralysis, and
for all fiber types during the second week of postnatal coincident with improving pulmonary status, this
fluid-saving influence is reduced, and the baboon inlife.
During 11days following premature delivery a t 140 fants enter a period when a diuresis of 10-15% of body
days of gestational age, the mean fiber area of dia- weight normally occurs in prematurely delivered huto man infants (unpublished observations). For the 11phragm muscle fibers decreased from 244'27
73
FIBER TYPES IN BABOON DIAPHRAGM
10000
z
-
ri
u)
E
(P
g
1000
5if
Prem
Term
Adult Female
Adult Male
E
Q
:
100
.1
10
1
100
Body Weight (Kg)
Fig. 5. Mean diaphragm muscle fiber area is plotted against body weight. The axes are logarithmic
due to the magnitude of the range of the data.
day group, weight stabilized a t somewhat lower than
initial birth weight during the latter days of support.
No significant differences in the proportion of fiber
types or mean fiber area were found amongst the seven
sampling sites within diaphragm muscles of any of the
major groups (Tables 3 and 4). This finding is consistent with data for rat diaphragm muscles (Metzger et
al., 1985) in which only one site had proportions of fiber
types different from the rest of the muscle, and with
data for cat diaphragm muscles (Sieck et al., 1983)
which had no differences amongst various regions.
Thus, in spite of any differences in recruitment pattern
or physiological function of crural and costal portions of
the diaphragm (Decramer et al., 19841, the muscle fibers of these portions develop similarly. There are several implications of this finding: different rates of development of specific regions of diaphragm muscles
relative to each other cannot account for impaired respiratory function of the diaphragm as a whole; easily
accessible sites for diaphragm sampling contain fibers
of representative physiological properties; contractile
properties and fatigability of bundles from the sample
site used in our previous (Maxwell et al., 1983) report
(equivalent to the current site 4) are representative of
diaphragm function; and, differences in sampling site
amongst earlier studies of primate diaphragm muscles
(Keens et al., 1978; Keens and Ianuzzo, 1979; Maxwell
et al., 1983,1984) do not likely contribute to differences
in results.
Although we did not systematically study the abdominal and pleural surfaces of the diaphragm muscles, we saw no evidence that major differences in composition occur in baboon diaphragm between these
surfaces. This is not surprising for diaphragm muscles
of premature and term baboons, which have not completely differentiated to adult fiber-type distributions.
Due to the predominance of type IIc fibers in diaphragm muscles of premature animals, a difference in
the percentage of type I fibers would be difficult to
detect. Sieck et al. (1983) found a higher percentage of
type I fibers on the abdominal surface of adult cat diaphragm muscles, whereas Metzger et al. (1985) reported a higher proportion of type I fibers on the thoracic surface of adult rat diaphragm muscles.
Apparently, there are species differences in the distribution of muscle fiber types across the diaphragm cross
section.
The alteration of the proportion of fiber types during
the third trimester of gestation continues into postnatal life. The diaphragm muscle of premature baboons
contains a high proportion of type IIc fibers. These fibers are highly oxidative and express high myofibrillar
ATPase activity after alkaline preincubation as well as
after acid preincubation. This lack of “acid reversal” is
characteristic of immature, developing muscle fibers
which contain fetal isozymes of myosin (Whalen et al.,
1981) and of transitional fibers (Kugelberg, 1976) undergoing transformation from type I to type I1 (or vice
versa). The low percentage of type I fibers in premature
baboon diaphragm is consistent with the results of our
earlier study and with the results of Keens et al. (1978)
and of Keens and Ianuzzo (1979) on premature human
diaphragm. Muscle fibers throughout the costal and
crural diaphragm of premature baboons are highly oxidative and are not intrinsically susceptible to fatigue
due t o low oxidative enzymatic capacity.
The diaphragm of term compared to premature baboons has a greater proportion of type I fibers and type
IIh fibers, but a reduced proportion of type IIc fibers.
These results are consistent with an ongoing differentiation and transformation of fiber types during gestation. Type IIc fibers likely differentiate into adult type
I and 110 fibers as gestation approaches full term. At
term, a few fibers demonstrate the histochemical characteristics of the less-oxidative type IIg fibers. This
suggests that the appearance of significant proportions
74
L.C. MAXWELL ET AL.
Type Ilo
80-
60-
wm
40-
200
l i
. . 110
wil
ldo
160
1 0‘0
Days Post-Conception
Fig. 6. The percentages of type I, 110, IIg, and IIc fibers are plotted as a function of postconceptional
age. Data obtained after intrauterine development are shown by filled symbols; those following extrauterine life are shown by open symbols. The data for 4 days of extrauterine life are the same as the data
used for Figure 3.
of type IIh (“halo”)fibers represents transition between
type 110 and type IIg characteristics. The halo appearance of fibers destined to become type IIg fibers may
result from growth of low oxidative muscle a t the periphery of muscle fibers, from the progressive loss of
oxidative capacity toward the central parts of the fibers, or both (Fig. 9). Evidence in support of this interpretation is that type IIh fibers are larger than type 110
fibers in both premature and term baboons. The timing
of the appearance of “halo fibers” in diaphragm muscles of human infants (Farkus-Bargeton, 1977) is also
consistent with this interpretation. Transformation of
type IIa to type IIb fibers has also been reported for
diaphragm muscle of young, growing rats (Tamaki,
1985).
After full term, the proportion of type I fibers stabilizes a t adult values, but the proportions of type I1 fibers continue to change. Diaphragm muscles of adult
baboons have very few type IIc fibers, a reduced proportion of oxidative (types 110 and IIh) fibers, and an
increased proportion of type IIg fibers relative to the
muscles of premature or term animals. The small proportion of type IIc fibers observed in adult muscles may
represent continuing transformation of fibers between
type I and I1 myosin isozymes. As respiratory function
approaches adult patterns, a large population of type
IIg and a smaller population of type 110 fibers characterize adult diaphragm muscles. The presence of a
large population of fatigable type IIg fibers in a muscle
as vital as the diaphragm is probably a consequence of
the large respiratory reserve volumes in adults. The
respiratory muscles are capable of generating pressure
gradients to rapidly move very large volumes of air if
all of their muscle fibers participate in the contraction.
However, respiratory muscles are not normally recruited to work at this maximal level, and normal respiration requires the contraction of only a fraction of
respiratory muscle fibers a t any instant in time. Less
frequently recruited fibers lose the capacity for high
levels of oxidative metabolism but remain available for
use during periods of increased respiratory drive. This
transition from type 110 to type IIg fibers during postnatal life represents an adaptation to lower recruitment levels, as occurs during detraining of diaphragm
and other skeletal muscles (Faulkner et al., 1972).
There are essentially no type IIh fibers in adult mus-
75
FIBER TYPES IN BABOON DIAPHRAGM
Type I
Type Ilo
r 100
o d . . 120
I
.
.
. . .160
I
.
.
! . .200,
180
140
Days Post-Conception
Fig. 7. The mean fiber areas of type I, 110, IIg, and IIc fibers are plotted as a function of postconceptional age. Data obtained after intrauterine development are shown by filled symbols; those following
extrauterine life are shown by open symbols. The data for 4 days of extrauterine life are the same as the
data used for Figure 4.
cles, further supporting our interpretation that these
exist during development when the peripheral growth
of the fibers contains relatively few mitochondria.
Muscle fibers of all types approximately double in
cross-sectional area during the last trimester of gestation. Much of this growth could be a normal consequence of maturation of muscle fibers. Whether spontaneous respiratory movements, which can be detected
during gestation in animals and humans (Harding,
19481, influence the growth of muscle fibers is not
known. There appears to be no effect of sex on muscle
fiber growth during prenatal development. Certainly,
the major growth of diaphragm muscle fibers occurs
during postnatal life when spontaneous breathing increases the frequency and force for which the diaphragm is recruited. During postnatal life, the diaphragm muscle fibers of male baboons grow larger
than the fibers in muscles of female baboons. This sexrelated difference in diaphragm muscle fiber growth
correlates with differences in body weight between
males and females. This difference could represent
greater respiratory load on the diaphragm muscle fi-
400
-
300
-
200
-
100
100
. .
I
120
140
.
.
,
.
.
160
I,
180
- ,.
.
.
I
200
Days Post-Conception
Fig. 8. The overall muscle fiber cross-sectional area (MFCSA) of
diaphragm muscle fibers is plotted as a function of postconceptional
age. Data obtained after intrauterine development are shown by filled
symbols; those following extrauterine life are shown by open symbols.
76
L.C. MAXWELL ET AL.
TYPE I I FIBER TRANSFORMATIONS
Ilc
I lo
Ilh
-Growth o f l e s s o x i d a t i v e periphery
-Loss o f c e n t r a l m i t o c h o n d r i a
Fig. 9. A schematic description of the transformation of type I1
fibers during prenatal development is shown.
bers of larger animals, different hormonal background
for the growth of muscle, or both.
The possibility that the activity of breathing may
influence the growth and development of respiratory
muscles is of concern for researchers investigating the
development of respiratory function and for clinicians
evaluating the respiratory capabilities of premature
infants. Striated muscle responds with a variety of
adaptive alterations to meet the demands placed upon
it (Baldwin et al., 1972; Faulkner et al., 1972; Maxwell
et al., 1973). Following premature birth, the work of
breathing represents a large increase in the work load
on respiratory muscles, and it is reasonable to question
whether adaptive changes in response to that increased
work demand alter the normal development of respiratory muscles. The results of the current study address
that question.
The proportions of fiber types in primate diaphragm
muscles change considerably during the third trimester of gestation (Keens et al., 1978; Keens and Ianuzzo,
1979; Maxwell et al., 1983). The proportions of fiber
types in baboon diaphragm also change during the first
11days following premature birth, but the proportions
of fiber types during extrauterine development after
premature delivery do not differ from those during intrauterine development alone a t a comparable postconceptional age (Fig. 5 ) . Possible explanations for this
could include the following: 1)the work of extrauterine
breathing does not represent an adequate stimulus; 2)
there is not time within 11 days for the adaptive response to be demonstrated; or 3) the developmental alterations in the muscles exert control over muscle fiber
characteristics which is not interrupted by changes in
functional demand. In view of the respiratory distress
and respiratory muscle fatigue common amongst premature infants (Derenne et al., 1978a-c), the possibility that premature birth does not represent an increased demand on the respiratory muscles seems
unlikely. Of course, the demand of breathing is lessened to the extent that mechanical respiratory assistance is required. For example, all premature baboons
delivered after 140 days of gestation received 2 days of
ventilatory assistance, and some animals required intermittent ventilatory assistance through the first 4
days of life. During such assistance, there may not be
an adequate stimulus for adaptation of respiratory
muscle fibers. The rate of change of enzymatic activities during adaptive responses depends upon the intensity of the stimulus and the ability of the muscle fibers
to alter protein metabolism. Diaphragm muscles in human respiratory patients requiring ventilation can
demonstrate a sufficient response to inspiratory resistive training to permit weaning from the ventilator
within as little as 10 days (Aldrich and Karpel, 1985).
Furthermore, the respiratory muscles of human and
baboon infants undergo rapid changes during the last
weeks of gestation (Keens et al., 1978; Keens and
Ianuzzo, 1979; Maxwell et al., 1983). Therefore, it
seems reasonable that 11 days is an adequate time to
permit demonstration of adaptive alterations, but the
effective stimulus was only delivered for 7-9 days.
There remains the third possibility, that the enzymatic
properties of respiratory muscle fibers are unable to
demonstrate adaptive responses after birth during the
third trimester of gestation. The muscle fibers during
this time are undergoing rapid alterations of fiber type.
The genetic control of the development of the muscle
fibers may be so strong that it cannot be interrupted by
altered demand. Whether adaptations of other characteristics occurred which were not measured, or whether
the extrauterine development might influence the final muscle composition during adult life, cannot be determined from the current data. However, the proportions of fiber types appear not to be altered during
extrauterine compared to intrauterine development.
An expected response to an increase in the load
against which muscle fibers must work is hypertrophy
of muscle fibers (James, 1979). However, muscle fibers
in the diaphragms of prematurely delivered baboons
were considerably smaller than muscle fibers following
only intrauterine development (Fig. 2). Even the muscle fibers of baboons sacrificed during the first few
hours after delivery were smaller than muscle fibers at
a comparable postconceptional age from our previous
study (Maxwell et al., 1983), in which animals were
terminated within the first few minutes after delivery.
This indicates that the decline in muscle fiber crosssectional area commenced almost immediately at delivery. Much of this decline in fiber area occurred during the period of paralysis, when the diaphragm was
not recruited. Thus, for the first 48 hours, an argument
could be supported that the muscle fibers undergo a
disuse atrophy. There was no evidence of recovery of
fiber area in any fiber type during the study period.
The initial decline of fiber area during the first 4 days
of extrauterine life was not the result of water loss,
since the hydration of the muscles at 4 days after premature delivery was unaltered from that immediately
after premature delivery. By 11days following premature delivery, the dry:wet ratio increased, indicating a
relative loss of 3%of muscle weight due to dehydration.
Dehydration cannot account for the decline of fiber
area during extrauterine life to 51-63% of the fiber
area for age-matched muscles during intrauterine development. Nor can dehydration account for the decline
of fiber area a t 6-9 days after full-term delivery, since
dry:wet ratio decreased during this time, indicating
relatively greater hydration.
There is also the possibility that the diaphragm muscle fibers were nutritionally deprived during the intensive neonatal care for 11days after premature delivery.
77
FIBER TYPES I N BABOON DIAPHRAGM
In adult hamsters underfed by 33%, body weight declined 25% and diaphragm weight by 29% within 4
weeks (Kelsen et al., 1985). Thus, relative undernutrition could contribute to the failure to maintain diaphragm muscle mean fiber area. This problem may be
more severe for the immature muscle fibers of premature baboons when the metabolic requirements for
growing, active muscle are increased. Perhaps the rigors of extrauterine life impose demands on muscle fibers after birth which are not adequately met by the
nutritional supply.
Mean fiber cross-sectional area (MFCSA) of diaphragm muscles from premature baboons only declined
to 65% of the fiber area for age-matched muscles after
intrauterine development, less than the relative decline for any fiber type. The greater loss of mean fiber
area (MFA) for type I fibers than of MFCSA can be
accounted for by considering the combined effects of
fiber atrophy and fiber-type transformation. As type IIc
fibers mature, they grow in cross-sectional area, and
they differentiate to other fiber types. Since type IIc
fibers are the smallest fibers, transformation of them to
type I or type 110fibers would have the effect of reducing the MFA of those types of fibers. This effect can also
be seen for type I fibers during intrauterine development when type I MFA remains constant (Fig. 7) during the third trimester, while MFCSA increases (Fig.
8).Furthermore, if it is assumed that the largest of the
type IIc fibers are the most likely to transform, then
the MFA of the type IIc fibers would not accurately
reflect muscle fiber growth. Thus, the reduction of
MFA likely results in part from fiber atrophy and in
part from transformation of small fibers to the enzymatic characteristics of larger ones.
Differentiation could occur either as the IIc fibers
grow to a set cross-sectional area or as the IIc fibers
reach a set postconceptional age (Fig. 10). The former
does not seem likely in view of our current data, since
no reduction in type IIc fiber area would be expected in
extrauterine compared to intrauterine development if
type IIc fibers had to achieve a predetermined fiber
area before differentiation could occur. The latter possibility is consistent with our data since the proportions of fiber types appear unaltered by extrauterine
development, but the fiber area is reduced. Thus, although fibers atrophy and the growth of fibers may be
retarded from normal during extrauterine development, the fiber transformations occur on schedule.
Although premature delivery does not appear to interfere with the normal development of fiber types, the
failure to maintain fiber growth leaves little doubt that
diaphragm muscle of premature baboons becomes less
able to meet contractile requirements during the period shortly after birth when the demands are increasing. The diaphragm function may be declining when it
is highly needed. This may also occur to some extent
even after normal term delivery. How long the relative
loss of muscle fiber area continues before recovery and
growth of fibers resumes cannot be determined without
longer-term studies.
ACKNOWLEDGMENTS
This work was supported by NIH grants HL 29977
and HL 38427.
GESTATIONAL AGE
0
0
.fO
..................
...........
...............
................
>
......
:.:.:.:.:.:.:.:
.................
.................
.............
....
t
Differentiation occurs at time "t" regardless of size
GESTATIONAL AGE
Differentiation occurs at size "s" regardless of time
Fig. 10. Two hypothetical schemes by which muscle fiber differentiation might be controlled during development are shown.
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fiber, muscle, distributions, baboons, developing, regional, diaphragm, typed
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