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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 4133-4138
Copyright © 1997 by The Endocrine Society

Original Studies

Contractile Properties and Fiber Type Distribution of Quadriceps Muscles in Adults with Childhood-Onset Growth Hormone Deficiency

R. Bottinelli, M. Narici, M. A. Pellegrino, B. Kayser, M. Canepari, G. Faglia and A. Sartorio

Istituto di Fisiologia Umana, Università di Pavia (R.B., M.A.P., M.C.), Pavia, Italy; Istituto di Tecnologie Biomediche Avanzate, National Research Council of Italy (M.N.); the Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore (M.F.); and the Endocrine Unit, Italian Institute for Auxology (A.S.), Milan, Italy; and the Departement de Physiologie, Centre Medical Universitaire, University of Geneva (B.K.), Geneva, Switzerland

Address all correspondence and requests for reprints to: Dr. Roberto Bottinelli, Istituto di Fisiologia Umana, Via Forlanini 6, I-27100 Pavia, Italy. E-mail: r.bottinelli{at}unipv.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Adults with GH deficiency (GHD) report weakness and fatigability. The origin of such symptoms is still debated. This work aimed to clarify whether weakness and fatigability depend on impairment of skeletal muscle contractile capacity. Five males with childhood-onset GHD (age ± SE, 29.6 ± 1.9) and 13 age- and sex-matched controls were enrolled in the study. Quadriceps muscle cross-sectional area (CSA), strength, twitch characteristics, and fatigue index of voluntary and electrically evoked contractions were determined in vivo in all subjects. Fiber type distribution and CSA of identified types of skeletal fibers were determined on needle biopsy samples of the vastus lateralis muscle of all subjects. Fiber type distribution was assessed on the basis of myosin heavy chain (MHC) isoform composition determined by electrophoresis on polyacrylamide gels. Fiber CSA was determined on cross-cryosections of fiber bundles immunostained by monoclonal antibodies against MHC isoforms. Absolute values of strength and fiber CSA of quadriceps were significantly lower in patients affected by GHD than in controls. However, once strength and fiber CSA were normalized for quadriceps CSA and subject height, respectively, differences disappeared. No difference was found between GHD patients and controls for quadriceps muscle twitch characteristics, fatigue index, and fiber type distribution. The results reported here suggest that weakness and fatigability in childhood-onset GHD do not have a skeletal muscle origin.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADULTS WITH GH deficiency (GHD), both childhood onset and the acquired syndrome, report weakness and fatigability despite conventional replacement therapy, but not GH substitution therapy (1, 2, 3). It is not known whether these symptoms are of central or peripheral origin and whether they are due to the lack of GH. In a recent work on the matter (4), an interesting hypothesis to account for fatigability has been put forward: as fast fibers are less fatigue resistant than slow fibers, fatigability of GHD patients might depend on an increase in fast fiber type proportion. However, such a hypothesis is difficult to verify for at least two reasons: 1) it has been uniquely based on the observed differences in functional properties, i.e. twitch characteristics and force-frequency relationship, of quadriceps muscles in GHD subjects and controls, whereas quadriceps fatigability and fiber type distribution have not been determined; and 2) knowledge of the effects of GHD on skeletal muscle fiber type distribution is very limited. Contradictory results have been obtained in animals (5, 6, 7, 8). In the only work to date in which fiber type distribution was studied in humans, i.e. adults with acquired GHD (9), skeletal fibers were simply classified as slow and fast, whereas two fast fiber types, 2A and 2B, are now known to exist (10). This is a relevant point, as for analogy with what found in small mammals (11), in humans type 2A fibers are also very likely to have much higher oxidative capacity and lower fatigability than type 2B fibers.

With regard to weakness, in most studies muscle strength was lower in GHD subjects than in controls (3, 4, 12, 13). However, the mechanism underlying skeletal muscle involvement in GHD is still little understood for several reasons. As in most studies muscle strength was not normalized over muscle cross-sectional area (CSA), the lower strength of GHD subjects might be due to an intrinsic impairment of muscle force capacity or, more simply, to the decrease in muscle mass known to occur in GHD (14). As it has been shown that in vitro slow fibers develop significantly lower specific tension (force over CSA) than 2A and 2B fibers (15) in patients with multiple pituitary hormone deficiencies, not only fatigability, but also strength might be influenced by changes in fiber type distribution due to concomitant sex hormone, thyroid hormone, or steroid replacement treatment (4, 13, 16, 17, 18, 19). Finally, as loading on skeletal muscle can per se change fiber type distribution and therefore the functional properties of skeletal muscles (20, 21), the possibility exists that differences in body mass index (BMI) (4, 13) determine muscle changes not due to a direct effect of GHD on skeletal muscle.

For the above reasons, this work, with the aim to further understand the origin of weakness and fatigability, focused on a very strictly selected, although necessarily limited, group of 5 patients with childhood-onset GHD and 13 controls. Not only strength and twitch characteristics, but also fatigability, fiber type distribution, and fiber CSA of quadriceps muscles were determined. Contractile properties of quadriceps and CSA of the thigh were determined in vivo. Fiber type distribution and fiber CSA were determined from needle biopsy samples of the vastus lateralis muscles of all subjects. In line with most recent studies (15, 22, 23, 24, 25, 26) myosin heavy chain (MHC) isoform content was used as marker of fiber type. Fiber type distribution, therefore, was assessed on the basis of the relative content in the three known human MHC isoforms (MHC-1, or slow isoform, and MHC-2A and MHC-2B, or fast isoforms) of the muscle samples determined by electrophoretical separation and densitometric scanning of MHC bands.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Five males with childhood-onset GHD (described in Table 1Go) were admitted to the study after giving informed consent. The study was approved by our local ethical committee and was performed in accordance with the Helsinki Declaration of 1975, as revised in 1983. All patients had received GH substitution therapy during childhood; previous GH therapy had been interrupted at least 7 yr before entry into the present study. Two patients had, in addition, associated hormone deficiencies and therefore received adequate stable substitution therapy. The data obtained were compared with those recorded in a healthy control group (n = 13; height, 176 ± 5.2 cm; weight, 74.20 ± 5.1 kg) matched for sex, age (29.1 ± 4.5 yr), BMI (23.95 ± 2.1), and activity, recruited among friends and colleagues.


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  		Table 1. Characteristics of the five patients with childhood-onset GHD enrolled in the study

 
Hormonal determinations

Serum GH and plasma insulin-like growth factor I levels were determined using commercial RIA kits [Sorin (Milan, Italy) and Nichols Institute (San Juan Capistrano, CA), respectively]; the intra- and interassay coefficients of variation were less than 5%.

Confirmation of GHD

Before entry into the present study, the diagnosis of GHD (GH peak <5 ng/mL) was confirmed in each subject by means of two GH stimulation tests (L-dopa plus propranolol, insulin-induced hypoglycemia, and/or GHRH); mean plasma insulin-like growth factor I levels of patients (43.3 ± 13.1 µg/L) were significantly lower (P < 0.001) than those recorded in normal adults (296.3 ± 66.2 µg/L; range, 174.0–397.2 µg/L).

Quadriceps muscle CSA

Muscle plus bone CSA (CSAM+B) of the dominant thigh at the proximal four tenth of femur length was calculated from circumference after subtraction of dorsal and ventral skinfolds, using a flexible metal tape and callipers (Holtain, UK). All measurements were carried out by the same operator, and the coefficient of variation was 0.2% for tight circumference, 3.3% for the dorsal skinfold, and 4.9% for the ventral skinfold. From the anthropometrically obtained CSAM+B (ant.CSAM+B), a magnetic resonance imaging (MRI)-predicted CSAM+B was calculated using the following equation: predicted MRI CSAM+B = (ant.CSAM+B - 48.289)/0.894, where CSAM+B is the anthropometric CSA, 48.289 is the intercept, and 0.894 is the slope of the linear (r2 = 0.8; P < 0.001) MRI-CSAM+B relationship (27).

Quadriceps muscle functional properties

Maximum voluntary contraction. The apparatus and the experimental approach employed to determine functional properties of quadriceps muscles have been previously described in detail (28, 29). Isometric maximal voluntary contraction (MVC) of the dominant quadriceps was measured at 110°, as this corresponds to the optimum joint angle for knee extensors isometric force generation (29). The subjects were strongly encouraged to produce the maximum possible effort and, having reached the top value, to make a brief all-out effort. Three MVCs, each lasting 5 s with 3-min intervals in between, were recorded at 10 mm/s on paper using the twitch superimposition technique (30) to ensure complete muscle activation. A MVC was defined as truly maximum if no extra torque was generated by the superimposed twitch (elicited by electrical stimulation). Only the highest of the three recorded values was retained for analysis.

Muscle twitch characteristics. Three supramaximal twitches, 30 s apart, were recorded at 110° of knee extension in each subject. For each twitch, maximum tension, time to peak tension, half-relaxation time, and total twitch duration were measured, and an average value was calculated for each parameter. A twitch tension to MVC ratio was also calculated.

Fatigability. To assess the resistance to fatigue, the quadriceps was stimulated at 20 Hz for 1 s every 2 s for 1 min. A fatigue index was calculated as the ratio of the final (30th contraction) over the initial (1st contraction) force.

Needle biopsy samples

Biopsy samples (50–100 mg) were taken from all subjects from the vastus lateralis muscle under local anesthesia (15) and divided into two parts. The largest part was put in 0.5 mL sample buffer (31) and subsequently used for electrophoretic determination of MHC and myosin light chain (MLC) isoform composition on polyacrylamide gels (SDS-PAGE). The other part of at least 100 fibers was embedded in gelatin and frozen in isopentane precooled by liquid nitrogen for subsequent immunohistochemical analysis.

MHC and MLC isoform distribution

According to most of the recent works, in the present study MHC isoforms were used as molecular markers of fiber type, and therefore, the MHC composition of the samples was used as an index of fiber type distribution (24, 32). Three bands corresponding to MHC-1, MHC-2A, and MHC-2B isoforms (15, 33) were separated by means of SDS-PAGE according to a method previously described in detail (34) (Fig. 1AGo). Densitometric scans of the electrophoretic bands and determination of the area under each densitometric peak were used to establish the relative proportions of the three MHC isoforms in the biopsy samples (32) (Fig. 1AGo).



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  		Figure 1. Electrophoretic separation (SDS-PAGE) of MHC (A) and MLC (B) isoforms of biopsy samples of vastus lateralis muscles of childhood-onset GHD patients. Lines and labels indicate the area of migration of the MHC (A) and MLC (B) isoforms. From left to right, densitometric traces, magnified image of the area of the gel from which the densitometric traces were obtained, and electrophoretic runs of samples from two vastus lateralis muscles with different MHC distributions (in A) and MLC distribution (in B) are shown. Densitometric traces and images refer to the left lane.

 
Five MLC isoforms are known to be expressed in human skeletal muscle: three isoforms of essential MLC [MLC-1f and MLC-3f (fast), and MLC-1s (slow)] and two isoforms of regulatory MLC [MLC-2s (slow) and MLC-2f (fast)]. In the present work, MLC isoforms were separated by SDS-PAGE on 10–20% linear polyacrylamide gradient slab gels (35) (Fig. 1BGo). Three MLC isoforms were clearly separated (MLC-2f, MLC-2s, and MLC-3f), whereas two comigrated in the same band (MLC-1s and MLC-1f). For MHC isoforms, densitometric scans were performed, and the relative contents of MLC-2s, MLC-2f, MLC-3f, and MLC-1s plus MLC-1f in the biopsy samples were determined (36).

Single fiber CSA

Cross-cryosections of bundles of at least 100 fibers were immunostained using 3 monoclonal antibodies against MHC isoforms (23, 37): BA-F8 against MHC-1, SC-71 against MHC-2A, and BF-G6 against MHC-2B. The staining procedure was described in detail previously (25). Three human fiber types, type 1, type 2A, and type 2B, could be identified, and there CSA were determined. About 100 fibers/subject were analyzed. CSA not only was expressed in absolute values (square microns), but was also normalized for the height of the subject (CSA/height2) to determine whether CSA was appropriately scaled for height.

Statistical analysis

Data were expressed as the mean and SD. Statistical significance of the differences was assessed by variance analysis followed by the Student-Newman-Keuls test. A probability of less than 5% (P < = 0.05) was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Quadriceps strength

Figure 2Go reports the mean MVC values of the quadriceps muscles of the 5 GHD subjects compared to those of the 13 controls. Quadriceps strength was significantly lower in GHD than in control subjects. However, when strength was normalized over CSA of the thigh, differences were not significant.



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  		Figure 2. MVC of quadriceps muscles in childhood-onset GHD and control subjects. In A, absolute MVC values are reported. In B, MVC values are normalized over muscle CSA. Stars indicate a significant difference from CTRL.

 
Twitch characteristics

Table 2Go reports the twitch characteristics of the quadriceps muscles of GHD and control subjects. Whereas the twitch force was significantly lower in GHD than in control subjects, no significant differences were found in time to peak tension, half-relaxation time, or total twitch duration.


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  		Table 2. Twitch force (Ptw), time to peak tension (TPT), half-relaxation time (1/2 RT), total twitch duration (TTD), fatigue index (FI), and twitch force over maximum voluntary contraction (Ptw/MVC) of quadriceps muscles of GHD and control subjects

 
Twitch to MVC ratio and fatigue index

The ratios between the twitch force and MVC were similar in GHD and control subjects (Table 2Go). No differences were found between GHD and control subjects in the fatigability of the quadriceps muscles (Table 2Go).

Fiber type distribution and fiber CSA

MHC isoform distribution was assessed from electrophoretic analysis of needle biopsy samples of vastus lateralis muscles (Fig. 1Go). MHC were used as markers of fiber type. The results reported in Fig. 3AGo indicate that in GHD subjects there was a slightly, but not significantly, higher percentage of fast type 2B fibers than that in controls. MLC distribution was not significantly different in the two groups, although a slightly higher percentage of the fast regulatory MLC (MLC2f) and a slightly lower percentage of the slow regulatory MLC (MLC2s) were found in GHD subjects compared to controls (Fig. 3BGo).



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  		Figure 3. MHC and MLC isoform distribution of quadriceps muscles of GHD and control (CTRL) subjects. MLC-1f and MLC-1s comigrated and are considered together.

 
CSAs of type 1 and type 2A were determined on immunostained cross-cryosections of bundles of about 100 fibers. CSAs of type 1 and type 2A fibers of GHD subjects were lower (-39% and -21%, respectively) than CSA of the corresponding fiber types in controls (Fig. 4AGo). However, when type 1 and type 2A muscle fiber CSAs were normalized for the square of the subject’s height, it was found that CSA/height2 of the GHD patients was not different from CSA/height2 of the controls. The number of type 2B fibers in cross-sections was too low (<10% in controls) to allow statistical analysis, and this fiber type was not considered for comparison.



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  		Figure 4. CSAs of single skeletal fibers from cross-cryosections of fiber bundles. A, Absolute values. B, CSA values normalized for subject height. Stars indicate a statistically significant difference (P < 0.05) between GHD and controls.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study male patients with childhood-onset GHD, homogeneous in age and previous treatment, were compared to controls matched for age, sex, BMI, and activity with regard to the contractile properties and fiber type distribution of quadriceps muscles and CSA of single fibers. The contractile properties were not different in GHD and control subjects. Fiber CSA was lower in GHD subjects, but the difference disappeared when CSA was normalized over body size. For the first time, fiber type distribution of skeletal muscle in GHD and control subjects was precisely determined, and no significant differences were found.

The present results strongly suggest that in patients with childhood-onset GHD 1) skeletal muscle function and fiber size are decreased proportionally to muscle mass and body size; 2) the fatigability of the quadriceps muscle, determined experimentally, is not higher than that in controls; and 3) the complaint of increased fatigability frequently reported by GHD patients does not depend on an increased percentage of fast (fatigable) fibers in skeletal muscles.

In all studies of functional properties of skeletal muscle in GHD, both muscle strength (3, 4, 12, 13) and power (16) have been found to be lower than those in controls. However, in most cases absolute values of strength and power have been used for comparison between GHD and control subjects. As muscle mass is lower in GHD, and strength and power are proportional to muscle CSA, it is expected that lower values are found in GHD. In agreement with previous findings (38) in the present study absolute values of quadriceps strength were lower in GHD than in controls, but once strength was normalized for thigh CSA, differences disappeared. In another previous study, normalized force was lower in subjects with acquired GHD than in controls (39). Such a discrepancy might derive from the different height, body size, and duration of uncorrected GHD of childhood onset vs. acquired GHD and from a possible submaximal activation of muscle fibers in the work by Cuneo et al. (39). In the latter work, at variance with the present study, maximal neural recruitment was not verified and relied only on the subject’s ability and motivation to produce a maximum effort.

In the present study, on the contrary to what observed in a previous study (9), absolute CSA values of both type 1 and type 2A fibers of the quadriceps were significantly lower in GHD subjects than in controls. Such a discrepancy might depend on the differences between childhood-onset (present study) and acquired (13) GHD subjects with regard to BMI and duration of uncorrected GHD. When the CSA values here reported were normalized over body size, differences between GHD and control subjects disappeared, suggesting that the size of the skeletal fibers was reduced proportionally to the decreased body size.

As in most recent studies (15, 24, 34, 40), MHC isoforms were used as molecular markers of fiber type. In relation to counting fibers in histochemically stained or immunostained sections, the SDS-PAGE approach offers the advantage that it accounts for the presence of hybrid fibers and for variation in fiber size (32), i.e. it gives a reliable idea of the proportion of myosin isoforms actually expressed in the muscles.

It is generally thought that needle biopsy samples taken from the same portion of the vastus lateralis muscle as in this study can be reliably used to compare MHC distribution of vastus lateralis muscles of different subjects. It has been shown, in fact, that duplicate samples from the same site of the vastus lateralis muscle of the same subject show a variability in MHC composition of 4–6%, which also comprises experimental errors due to the technique used (41). MHC isoform distribution of needle biopsy samples has been used to compare muscle fiber type distribution 1) before and after physical training (42, 43), 2) of young and elderly individuals (37), 3) of prior polio patients and control healthy subjects (44), and 4) of different muscles in the same subject (32). This study shows that the determination of MHC isoform distribution provides interesting information in GHD patients also. As these patients have a MHC isoform distribution similar to that of controls, modifications of skeletal muscle contractile properties in childhood-onset GHD are unlikely to be accounted for by a shift in fiber type distribution. Such a conclusion is confirmed by the analysis of MLC distribution, which is also an index of fiber type distribution (33).

In small mammals, an increase in fast fiber type relative content has been suggested in GHD (5, 6). However, contradictory results have been reported (7, 8). As far as fiber type distribution is concerned, the present results are in agreement with the only data available in humans (9). Although Cuneo et al. (9) identified only two of the three human fiber types, they showed no change at least in type 1 fiber proportion before and after GH treatment in adults with GHD.

A very recent work on the basis of lower half-relaxation time and rightward shift of force-frequency relation of quadriceps muscles in GHD subjects compared to those in controls suggested an increase in fast fiber proportion (4). The researchers hypothesize that as fast fibers are less fatigue resistant than slow fibers, such an increase in fast fiber proportion might explain the fatigability reported by the patients. The present results show that such a hypothesis does not apply to the idiopathic childhood-onset GHD. In fact, in quadriceps muscles, fatigue, twitch characteristics, MVC/CSA, and fiber type distribution of patients with childhood-onset GHD were not significantly different from those of controls. The normal muscle twitch kinetics and fatigability in the quadriceps of the GHD subjects of the present study is fully consistent with the lack of a significant shift in fiber type proportion. The discrepancy between the present findings and those reported by Rutherford et al. (4) seems noteworthy and may be due to the different populations considered. In this study only male subjects with childhood-onset GHD, similar age (29.6 ± 4.5 yr), and similar previous treatment history were considered. Subjects with both childhood-onset and acquired GHD, of both sexes, older average age, and higher age variability (41 ± 17.3 yr) were considered in the work by Rutherford et al. (4).

It seems likely, therefore, that the frequently reported complaint of increased fatigability is not of peripheral origin, i.e. involving the structure and function of skeletal muscle, but is of central origin, and as such may involve both cardiovascular as well as neural factors (38, 45). This study strengthens the idea that, with regard to skeletal muscle function and fiber type distribution, patients with childhood-onset GHD are appropriately scaled for their heights.


   Acknowledgments
 
We thank Dr. Carlo Reggiani for reading the manuscript and for very valuable criticisms and suggestions, and Ms. Liliana Lo Baido for technical help.

Received May 6, 1997.

Revised August 11, 1997.

Accepted August 26, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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