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Studies of the cardiac effects of GH administered to children without GH deficiency probably serve as a better model for the role of GH in the normal course of cardiac development with somatic growth. Daubeney et al. reported echocardiographic measures of heart size in 15 children with short stature (but no GH deficiency) before and after four years of GH treatment, compared with an untreated group (22). No anthropometric or ventricular-dimension differences were observed between the two groups at baseline. After four years of GH treatment, however, the treated children exhibited greater height, weight, and lean body mass as well as larger left ventricular end-diastolic dimension (41 ± 5 mm vs. 36 ± 5 mm) and left ventricular mass (93 ± 33 g vs. 73 ± 26 g).
Posttreatment left ventricular mass expressed relative to lean body mass was similar to that of the controls, however, suggesting that increases in heart size reflected changes in lean body mass with GH treatment. No alterations in ventricular shortening fraction (an indicator of systolic contractile function) were observed following hormone treatment.
Similar results were observed in short children by Barton et al., who found that increases in cardiac dimensions with GH treatment paralleled those of body size (4).These findings in short but otherwise normal children mimic those in rats with GH-secreting tumors, who show accelerated heart growth in pro¬portion to increases in body dimensions (72). They also simulate empiric observations during the growth of normal children: increasing heart size in relation to body dimensions (particularly lean body mass) without changes in myocardial contractility.
In abnormal hearts, GH increases myocardial function and improves energy efficiency. In the presence of left ventricular hypertrophy and failure, GH administered to both humans and animals causes a shift in myocardial myosin composition (increased V3 isoform and enhanced troponin I and myosin light chain 2), all changes associated with greater efficiency of myocardial contraction. These salutary effects of GH suggest its potential as a therapeutic modality for patients with depressed myocardial function (41). Fazio et al. administered recombinant GH to seven adult patients with idiopathic dilated cardiomyopathy and mild to severe congestive heart failure (29). Serum IGF-I concentrations doubled in response.Ventricular wall thickness increased, and a reduction was observed in end-diastolic dimension. Cardiac output during exercise improved 31 %, while myocardial oxygen uptake at rest fell by one third.
The cardiac effects of IGF-I are similar to those of GH. IGF-I enhances myocardial protein synthe¬sis and contractile function, both in normal hearts and in those with myocardial dysfunction (23). For example, Donath et al. found that IGF-I administered to healthy adults resulted in an 18% rise in cardiac output in association with a 9% increase in ventricu¬lar ejection fraction (23). Maximal oxygen uptake and exercise endurance, however, were not altered.
A host of locally acting growth factors have been identified that can mediate cardiac rnyocyte hypertrophy (at least in vitro), including cytokines, catecholamines, angiotensin II, and IGF-I (36).The increase in heart muscle cell size (i.e., hypertrophy) from such factors in response to hemodynamic over¬load may, however, not be an appropriate model for assessment of increases in cell size that occur with normal growth. Stress-related responses involve specific alteration in gene expression, which alters the phenotypic expression of contractile proteins. The extent to which such alterations occur with normal growth in humans is uncertain. It is of inter¬est, however, that stress-induced changes in forms of myosin are often characterized by a reversal to fetal gene expression.
Increases in contractility in response to IGF-I exposure are dose dependent and reach about 20% to 25% above baseline. Alterations of calcium flux appear to be responsible.This improvement in myo¬cardial contractile function occurs despite absence of change in ATP content or high-energy phosphates, thus indicating greater energy efficiency.
Muscular Growth
Growth of skeletal muscle mass is one of the most firmly established activities of the GH/IGF-I axis (84).While animal studies indicate that GH has some primary effects, IGF-I appears to be predominantly responsible for the growth and development ofmuscle cells seen with exogenous or endogenous exposure to GH.This activity reflects both augmented protein synthesis through increased amino acid transport and inhibited cellular protein degradation.
Short stature is the most common feature of children with growth hormone deficiency, but these patients also demonstrate delayed motor develop¬ment and reduced muscle strength.These conditions are typically reversed by GH treatment. Brat et al. measured isometric muscle force and endurance in a small group of children with GH deficiency before and after 10 and 24 months of GH treatment (8). Before treatment, the muscle force of children with GH deficiency was 56% to 62% of that of matched healthy children. Strength measurements rose to 75% to 78% after 10 months of treatment and to 87% to 93% at 24 months.
A deficiency of GH is not necessary for these treatment effects. Leger et al. (45) assessed the effects of three years of GH treatment (0.2 IU • kg 1• d-') on muscle mass in 14 prepubertal children who were born small for gestational age (SGA). Muscle mass in this study was determined by magnetic resonance imaging. Results were compared with longitudinal measurements of children of normal stature. The increase in muscle cross-sectional area was 72 ± 5 % in the GH-treated SGA children compared with 22 ± 5 % in the controls.
The pharmacologic dose of GH in this study was approximately twice that used for replacement therapy in children who are GH deficient. In a previous publication, Leger et al. described a more rapid change in muscle size in SGA children than in GH-deficient children (46).This caused the authors to suggest that it is possible that the effect of GH on muscle in children is dose dependent.
Paracrine and autocrine factors acting locally and independently of GH may also be important for muscle growth. For example, mechanogrowth factor (MGF), produced in response to muscle stretch, has been demonstrated to stimulate muscle protein synthesis (34).
Adams reviewed data regarding the role of IGF¬I in mediating skeletal muscle adaptations to work stress (1). In rats, IGF-I stimulates muscle protein synthesis, increases amino acid uptake, and sup¬presses protein degradation. Furthermore, IGF-I has a separate action in promoting cell proliferation (mitogenesis) and differentiation in the embryonic development of skeletal muscle. Increasing evidence exists that these same two processes are involved in muscle adaptive responses to increased workload.
These investigations suggest that paracrine or autocrine actions rather than circulating IGF-I stimulate anabolic effects leading to muscle hyper¬trophy with work stress. In addition, IGF-I has been demonstrated to stimulate proliferation of satellite cells: small, mononucleated stem cells that have the capacity to proliferate and differentiate into myoblasts in response to work stress or injury.
Accounting for Interindividual Fitness Differences in Children
So far, the development of physiologic and physical fitness in children has been examined as an out¬come of increases in body size. Somatic maturation is largely responsible for longitudinal changes in exercise functional capacity during the growing years. This analysis, however, does not address fac¬tors that are responsible for individual differences in physical fitness.
If the somatic expression of growth factors was the only determinant of development of physiologic and performance fitness, all children of the same size would exhibit identical levels of fitness.This is clearly not the case. Any physiologic factor varies signifi¬cantly in respect to a given appropriate measure of body size. How can we explain such variations in fitness relative to the same body dimensions in any group of children of even identical chronologic or biologic age? Several possible answers can be con¬sidered.
1. Specific factors, which act independently of determinants of height and weight, may target their effects on the growth of fitness-related tissues. Such agents have been recognized, in fact. A number of peptide growth factors, particularly fibroblast growth factor 6 and epidermal growth factor, have been iden¬tified in cardiac myocytes (7).These factors have been implicated in hypertrophic responses of the heart to systolic overwork (systenuc hypertension) as well as fetal cardiac organogenesis. In any event, they provide evidence that localized, tissue-specific factors exist that can stimulate heart growth.
2. GH receptors may be selectively more popu¬
lous or active in the fitness-related tissues of children who exhibit superior levels of fitness. This would result in disproportionate growth of heart or muscle size, for example, relative to height and weight.
3. Size-independent factors may operate more prominently in children with greater fitness. As noted earlier, the development of size-independent factors may contribute significantly to the evolution of exercise fitness during childhood.The nature and magnitude of these size-independent influences vary among types of fitness. Interindividual variations in fitness could then relate to greater or lesser input from these factors, presumably on a genetic basis.The child with 50-yd dash performance superior to that of another child her own age and size might possess greater glycolytic capacity to provide anaerobically derived energy. A more developed level of neuro¬muscular input to muscles might explain the stronger child. This would not, however, explain differences in aerobic fitness, in which the influence of lung or heart size on VOzmax is predominant.
This issue is a critical one for developmental exercise physiologists, for it bears on the central question of identifying limiting factors to physical and physiologic performance by growing children. Because these interindividual differences in fitness are observed in nontrained youth in populations homogeneous in nutrition, socioeconomic status, and body composition, it is reasonable to conclude that, by whatever phenotypic mechanism, these dif¬ferentiating factors are under genetic control. Much progress has been made in determining specific gene loci that influence physical fitness (65). It is possible that this research will identify specific gene markers that define individual levels of fitness via one or more of the preceding mechanisms.
Effects of Exercise on Growth
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