Skeletal maturity and bone growth in twins

Heritability of skeletal maturity and bone growth is discussed on the basis of intrapair resemblances (correlation coefficients) and differences (revised percent deviations) in mono- and dizygotic twins and random pairs of unrelated children. A series of 1072 radiographs of the right hand and wrist in 63 male and 70 female pairs of monozygotic twins, and 25 male and 21 female pairs of dizygotic twins aged 12 to 18 years studied longitudinally in Tokyo were used. Skeletal maturity based on the TW2 age suggests higher heritability than bone growth based on the second metacarpal dimensions. In the latter, length has higher heritability than width and cortical thickness. A dosage effect seems to be suggested in width and some indices in the second metacarpal, but is not confirmed in skeletal maturation.     

Skeletal maturity of Japanese children in Western Kyushu

This paper describes the skeletal maturity status of Japanese children in Western Kyushu and its variation within Japanese populations. Hand-wrist skeletal maturity was assessed by the Tanner-Whitehouse (1975) (TW2) method from radiographs of 500 boys and 485 girls aged from 4 to 15 years. Western Kyushu children showed retarded skeletal maturity scores (RUS, carpals, and 20-bone) under the age of 12 years for boys and 10 years for girls, and thereafter they were advanced in relation to the British standard. Within Japanese populations the present sample showed delayed maturity compared to Tokyo children, but was close to that of Sapporo children throughout the age range studied. However, the expected effect of secular trend suggested skeletal maturity more advanced for Tokyo children and somewhat advanced one for Sapporo children compared to that of Western Kyushu children.     

Development of the hand and wrist bones in chimpanzees

Skeletal developmental of chimpanzees was studied cross-sectionally. By application of the TW2 method, we described the skeletal development of chimpanzees and compared their skeletal development with humans'. A development pattern of chimpanzees repeated accelerations and decelerations displaying “early-juvenile trough,” “pre-adolescent peak,” “mid-adolescent trough,” and “post-adolescent peak” in incremental curves. Sex differences in skeletal development are slower development in males during infant and early juvenile phases, and greater increment around the adolescent phase in males. Females are fully mature at younger ages than males, e.g. about one and a half years. In comparison with chimpanzees, humans have such characteristics as a longer slower period of juvenile development and a shorter spurt-like adolescent fast period which ends with full maturity.     

Problems in the aging of females using the Os pubis.

The Gilbert-McKern method for aging the female Os pubis has attained popularity following Gilbert's ('73) demonstration that the McKern-Stewart male standards are not directly applicable to females. In order to assess the reliability of the method, forensic anthropologists were asked to age a set of 11 pubes of known age. There was a great deal of variability in the responses of the 23 participants. Three, four, and five different responses (out of a 6-scale system) were given for each component of each pubic bone. Only 51% of the assessments yielded age ranges which would include the known age of the specimens. Analysis of the errors showed that one of the focal problems of the Gilbert-McKern system was the difficulty in judging whether the ventral rampart was building up or breaking down.     

Height, weight, and lines of arrested growth in young Guatemalan children

A cross-sectional study of height, weight and skeletal maturity as judged from radiographs of hand and wrist, of 1,412 children under seven years of age (694 boys and 718 girls) living in rural Guatemala was performed. Height and weight were compared to standards prepared by the Institute of Nutrition of Central America and Panama (INCAP). Skeletal age was assessed by the Tanner-Whitehouse and the Greulich and Pyle methods. All x-rays were read by the senior author. The children surveyed were significantly shorter and lighter than well noruished Guatemalan children. Differences were evident by age six months and at a maximum by age five years. Both methods showed skeletal age to lag behind chronological age so that the Guatemalan rural children mature at slower rates than either the British children or the Ohio, U.S.A., children, from whom the two sets of standards were developed. Children of both sexes with radio-opaque transverse lines at the metaphysis showed a consistent tendency to be shorter than children without such lines. Boys but not girls showed similar trends for weight. In general, the data are consistent with the view that the physical development in boys is more severely retarded by an adverse environment than that of girls.     

Regulation of the Skeletal Muscle Ryanodine Receptor/Ca2+-release Channel RyR1 by S-Palmitoylation

The ryanodine receptor/Ca²⁺-release channels (RyRs) of skeletal and cardiac muscle are essential for Ca²⁺ release from the sarcoplasmic reticulum that mediates excitation-contraction coupling. It has been shown that RyR activity is regulated by dynamic post-translational modifications of Cys residues, in particular S-nitrosylation and S-oxidation. Here we show that the predominant form of RyR in skeletal muscle, RyR1, is subject to Cys-directed modification by S-palmitoylation. S-Palmitoylation targets 18 Cys within the N-terminal, cytoplasmic region of RyR1, which are clustered in multiple functional domains including those implicated in the activity-governing protein-protein interactions of RyR1 with the L-type Ca²⁺ channel Ca_V1.1, calmodulin, and the FK506-binding protein FKBP12, as well as in “hot spot” regions containing sites of mutations implicated in malignant hyperthermia and central core disease. Eight of these Cys have been identified previously as subject to physiological S-nitrosylation or S-oxidation. Diminishing S-palmitoylation directly suppresses RyR1 activity as well as stimulus-coupled Ca²⁺ release through RyR1. These findings demonstrate functional regulation of RyR1 by a previously unreported post-translational modification and indicate the potential for extensive Cys-based signaling cross-talk. In addition, we identify the sarco/endoplasmic reticular Ca²⁺-ATPase 1A and the α_1S subunit of the L-type Ca²⁺ channel Ca_V1.1 as S-palmitoylated proteins, indicating that S-palmitoylation may regulate all principal governors of Ca²⁺ flux in skeletal muscle that mediates excitation-contraction coupling.     

Brachymesophalangia V in Hottentot and “Cape Colored” children in Namibia (South West Africa) and South Africa

In order to determine the incidence of Brachymesophalangia V, an inspectional and metrical analysis was made of radiographs of 67 Nama-speaking Hottentots aged 2 to 17.5 years, and 210 Rehoboth Basters (in Namibia) and Cape Colored children (near Cape Town) aged 1.5 to 21 years. None of the children displayed cone-shaped epiphysis or early union, and none showed Brachymesophalangia V. It was confirmed that the incidence of Brachymesophalangia V is considerably higher in Mongoloid populations than in Caucasoid or Negroid groups, including Hottentots.     

Clinical standards for growth in height of Belgian boys and girls,aged 2 to 18 years

The present paper presents the first clinical standard for growth in height of Belgian boys and girls, based on purely longitudinal data. Growth charts are provided with centiles of height for age along with growth curves of the typical early, average and late maturing child in the population. These new standards show the classical features of cross-sectional standards, but above that, they also provide information about the variability in individual growth patterns, as a result of variation in maturation. Average adult height is 176.6 cm (SD=6.3 cm) in boys and 163.3 cm (SD=5.7 cm) in girls. The representativity of these new standards with respect to the actual Belgian population has been by comparison with recent cross-sectional data, collected on a large number of subjects. These standards should be applied in all situations where interest lies in the evaluation of the normality of a child's growth pattern over some length of time and will therefore find their usefulness in clinical follow-up studies of growth.     

Subcutaneous fat remodelling in Southeast Asian infants and children

Longitudinal data on 1,048 Thai children were evaluated for evidence of subcutaneous fat remodelling. Fat distribution, as defined by 100 (triceps/[triceps + subscapular]), was more pronounced in the limbs during infancy but shifted toward the trunk thereafter. Subsequent stepwise regression analysis indicated that biological age--as measured by Gruelich-Pyle bone age--and weight together explained between 0.8% and 14.5% of variance in fat distribution, with generally larger R2 values over age and for males. Relationships were curvilinear, with sex differences in slope. Path analysis supported the model that weight was a major causal agent primarily after infancy, whereas biological age had a small influence both in infancy and in late childhood. These findings indicate that trunk fat deposition is a normal feature of childhood. They also suggest that hypotheses which associate elevated trunk fatness with disorders of glucose metabolism are invalid for younger children.     

Angiotensin Type 2 Receptor Signaling in Satellite Cells Potentiates Skeletal Muscle Regeneration

Patients with advanced congestive heart failure (CHF) or chronic kidney disease (CKD) often have increased angiotensin II (Ang II) levels and cachexia. Ang II infusion in rodents causes sustained skeletal muscle wasting and decreases muscle regenerative potential through Ang II type 1 receptor (AT1R)-mediated signaling, likely contributing to the development of cachexia in CHF and CKD. However, the potential role of Ang II type 2 receptor (AT2R) signaling in skeletal muscle physiology is unknown. We found that AT2R expression was increased robustly in regenerating skeletal muscle after cardiotoxin (CTX)-induced muscle injury in vivo and differentiating myoblasts in vitro, suggesting that the increase in AT2R played an important role in regulating myoblast differentiation and muscle regeneration. To determine the potential role of AT2R in muscle regeneration, we infused C57BL/6 mice with the AT2R antagonist PD123319 during CTX-induced muscle regeneration. PD123319 reduced the size of regenerating myofibers and expression of the myoblast differentiation markers myogenin and embryonic myosin heavy chain. On the other hand, AT2R agonist {"type":"entrez-protein","attrs":{"text":"CGP42112","term_id":"874777115","term_text":"CGP42112"}}CGP42112 infusion potentiated CTX injury-induced myogenin and embryonic myosin heavy chain expression and increased the size of regenerating myofibers. In cultured myoblasts, AT2R knockdown by siRNA suppressed myoblast differentiation marker expression and myoblast differentiation via up-regulation of phospho-ERK1/2, and ERK inhibitor treatment completely blocked the effect of AT2R knockdown. These data indicate that AT2R signaling positively regulates myoblast differentiation and potentiates skeletal muscle regenerative potential, providing a new therapeutic target in wasting disorders such as CHF and CKD.     

Further observations on a method for estimating hominoid dental developmental patterns

Several recent studies have concluded that early hominines resembled apes in patterns of dental ontogeny and have inferred from this conclusion that they were ape-like in other aspects of growth and development as well. Prior to their employment on fossil junveniles, the comparative methods used in these studies were not first tested for their predicitive accuracy in distinguishing modern humans from apes on the basis of proposed patterns of dental ontogeny. We find that 92% of a smaple of 48 modern children are classified as ape-like or nonhuman by the criteria employed in one of these studies and overlap entirely with fossil juvenile dental patterns. The use of these methods to characterize early hominines as “ape-like” or distinctly divergent from humans is thus shown to be unwarranted. © 1993 Wiley-Liss, Inc.     

Clinical standards for growth velocity in height of Belgian boys and girls,aged 2 to 18 years

The present paper presents the first clinical standards for growth velocity in height of Belgian boys and girls, based on purely longitudinal data. Growth charts are provided with centiles of height for age, along with the growth velocity curves of the typical early, average and late maturing child in the population. These new growth velocity standards provide centile lines which allow to judge whether a child's growth velocity over a one-year interval lies within the limits of normal variation for his age, irrespective of his stage of maturation. They also provide information about variability in the individual patterns of growth velocity in the population and can, as such, also be used to evaluate the normality of a child's pattern in growth velocity over a longer period of time. Age at peak velocity occured in 95% of the children within an age range of about 4 years. The average age at peak height velocity at puberty was 14.0 years (S.D.=1.0) in boys and 11.6 years (S.D.=0.9) in girls. Peak height velocity was in the average 9.1 cm/year (S.D.=1.4) in boys and 7.5 cm/year (S.D.=1.1) in girls. The representativity of these new standards with respect to the actual Belgian population was tested by comparison with recent cross-sectional data, collected on a large number of subjects. These new charts will find useful applications in longitudinal health screening surveys, and in clinical follow-up studies, where interest lies in the examination of a child's growth retardation in relation to some disease, or catch-up growth, as a response to subsequent medical treatment.     

Analysis of Local Structure in the D2/S1–S2 Region of the Rat Skeletal Muscle Type 1 Sodium Channel Using Insertional Mutagenesis

Abstract: A reporter epitope was inserted at 11 positions in a region encompassing proposed transmembrane segments S1 and S2 in the second repeat domain (D2) of the rat skeletal muscle type 1 sodium channel. All mutations produced full-length membrane-associated protein following transfection into cultured cells, although the level of expression varied with insertion position. Characterization of cognate cRNAs for each mutation in Xenopus oocytes by two-electrode voltage clamp defined a permissive region between the proposed transmembrane regions in which these large insertions did not interfere with channel function. Two of the mutations, in which the point of insertion was within the proposed S1–S2 loop, demonstrated extracellular membrane labeling when studied either by antibody binding in oocytes or by confocal analysis following transfection into primary muscle cells. Our results define the likely boundaries of an extramembrane region linking the S1 and S2 transmembrane segments in D2 and confirm the extracellular location of this S1–S2 loop predicted by current models of channel tertiary structure.     

Ca2+ Overload and Sarcoplasmic Reticulum Instability in tric-a Null Skeletal Muscle

The sarcoplasmic reticulum (SR) of skeletal muscle contains K⁺, Cl⁻, and H⁺ channels may facilitate charge neutralization during Ca²⁺ release. Our recent studies have identified trimeric intracellular cation (TRIC) channels on SR as an essential counter-ion permeability pathway associated with rapid Ca²⁺ release from intracellular stores. Skeletal muscle contains TRIC-A and TRIC-B isoforms as predominant and minor components, respectively. Here we test the physiological function of TRIC-A in skeletal muscle. Biochemical assay revealed abundant expression of TRIC-A relative to the skeletal muscle ryanodine receptor with a molar ratio of TRIC-A/ryanodine receptor ∼5:1. Electron microscopy with the tric-a^−/− skeletal muscle showed Ca²⁺ overload inside the SR with frequent formation of Ca²⁺ deposits compared with the wild type muscle. This elevated SR Ca²⁺ pool in the tric-a^−/− muscle could be released by caffeine, whereas the elemental Ca²⁺ release events, e.g. osmotic stress-induced Ca²⁺ spark activities, were significantly reduced likely reflecting compromised counter-ion movement across the SR. Ex vivo physiological test identified the appearance of “alternan” behavior with isolated tric-a^−/− skeletal muscle, i.e. transient and drastic increase in contractile force appeared within the decreasing force profile during repetitive fatigue stimulation. Inhibition of SR/endoplasmic reticulum Ca^{2+ ATPase} function could lead to aggravation of the stress-induced alternans in the tric-a^−/− muscle. Our data suggests that absence of TRIC-A may lead to Ca²⁺ overload in SR, which in combination with the reduced counter-ion movement may lead to instability of Ca²⁺ movement across the SR membrane. The observed alternan behavior with the tric-a^−/− muscle may reflect a skeletal muscle version of store overload-induced Ca²⁺ release that has been reported in the cardiac muscle under stress conditions.     

Selective Dephosphorylation of the Subunits of Skeletal Muscle Calcium Channels by Purified Phosphoprotein Phosphatases

Abstract: Multiple sites on the α1 and β subunits of purified skeletal muscle calcium channels are phosphorylated by cyclic AMP-dependent protein kinase, resulting in three different tryptic phosphopeptides derived from each subunit. Phosphoprotein phosphatases dephosphorylated these sites selectively. Phosphoprotein phosphatase 1 (PP1) and phosphoprotein phosphatase 2A (PP2A) dephosphorylated both α1 and β subunits at similar rates, whereas calcineurin dephosphorylated β subunits preferentially. PP1 dephosphorylated phosphopeptides 1 and 2 of the α1 subunit more rapidly than phosphopeptide 3. In contrast, PP2A dephosphorylated phosphopeptide 3 of the α1 subunit preferentially. All three phosphoprotein phosphatases preferentially dephosphorylated phosphopeptide 1 of the β subunit and dephosphorylated phosphopeptides 2 and 3 more slowly. Mn²⁺ increased the rate and extent of dephosphorylation of all sites by calcineurin so that >80% dephosphorylation of both α1 and β sub-units was obtained. The results demonstrate selective dephosphorylation of different phosphorylation sites on the α1 and β subunits of skeletal muscle calcium channels by the three principal serine/threonine phosphoprotein phosphatases.     

Store-operated Ca2+ Entry in Malignant Hyperthermia-susceptible Human Skeletal Muscle

In malignant hyperthermia (MH), mutations in RyR1 underlie direct activation of the channel by volatile anesthetics, leading to muscle contracture and a life-threatening increase in core body temperature. The aim of the present study was to establish whether the associated depletion of sarcoplasmic reticulum (SR) Ca²⁺ triggers sarcolemmal Ca²⁺ influx via store-operated Ca²⁺ entry (SOCE). Samples of vastus medialis muscle were obtained from patients undergoing assessment for MH susceptibility using the in vitro contracture test. Single fibers were mechanically skinned, and confocal microscopy was used to detect changes in [Ca²⁺] either within the resealed t-system ([Ca²⁺]_t-sys) or within the cytosol. In normal fibers, halothane (0.5 mm) failed to initiate SR Ca²⁺ release or Ca²⁺_t-sys depletion. However, in MH-susceptible (MHS) fibers, halothane induced both SR Ca²⁺ release and Ca²⁺_t-sys depletion, consistent with SOCE. In some MHS fibers, halothane-induced SR Ca²⁺ release took the form of a propagated wave, which was temporally coupled to a wave of Ca²⁺_t-sys depletion. SOCE was potently inhibited by “extracellular” application of a STIM1 antibody trapped within the t-system but not when the antibody was denatured by heating. In conclusion, (i) in human MHS muscle, SR Ca²⁺ depletion induced by a level of volatile anesthetic within the clinical range is sufficient to induce SOCE, which is tightly coupled to SR Ca²⁺ release; (ii) sarcolemmal STIM1 has an important role in regulating SOCE; and (iii) sustained SOCE from an effectively infinite extracellular Ca²⁺ pool may contribute to the maintained rise in cytosolic [Ca²⁺] that underlies MH.     

Three Types of Single Voltage-Dependent Potassium Channels in the Sarcolemma of Frog Skeletal Muscle

Patch-clamp experiments in the sarcolemma of frog skeletal muscle evidenced the presence of three types of voltage-dependent single-channel K⁺ currents. According to their unitary conductance at a membrane voltage of +40 mV, we classified them as 16-, 13-, and 7-pS K⁺ channels. The 16-pS K⁺ channels are active close to a membrane voltage of −80 mV and they do not become inactivated during voltage pulses of 100 ms. Within 10 min after beginning the recording, these channels developed rundown with an exponential time course. The 13-pS K⁺ channels are active near −60 mV; upon a 100-ms depolarization, they exhibited inactivation with an approximate exponential time course. The 7-pS K⁺ channels were recorded at voltages positive to 0 mV. In patches containing all three types of K⁺ channels, the ensemble average currents resemble the kinetic properties of the macroscopic delayed rectifier K⁺ currents recorded in skeletal muscle and other tissues. In conclusion, the biophysical properties of unitary K⁺ currents suggest that these single-channel K⁺ currents may underlie the macroscopic delayed K⁺ currents in frog skeletal muscle fibers. In addition, since the 16- and 13-pS channels were more frequently recorded, both are the main contributors to the delayed K⁺ currents.     

Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes

Growth/differentiation factors 5, 6, and 7 (GDF5/6/7) represent a distinct subgroup within the bone morphogenetic protein (BMP) family of secreted signaling molecules. Previous studies have shown that the Gdf5 gene is expressed in transverse stripes across developing skeletal elements and is one of the earliest known markers of joint formation during embryonic development. Although null mutations in this gene disrupt formation of some bones and joints in the skeleton, many sites are unaffected. Here, we show that the closely related family members Gdf6 and Gdf7 are expressed in different subsets of developing joints. Inactivation of the Gdf6 gene causes defects in joint, ligament, and cartilage formation at sites distinct from those seen in Gdf5 mutants, including the wrist and ankle, the middle ear, and the coronal suture between bones in the skull. Mice lacking both Gdf5 and Gdf6 show additional defects, including severe reduction or loss of some skeletal elements in the limb, additional fusions between skeletal structures, scoliosis, and altered cartilage in the intervertebral joints of the spinal column. These results show that members of the GDF5/6/7 subgroup are required for normal formation of bones and joints in the limbs, skull, and axial skeleton. The diverse effects on joint development and the different types of joints affected in the mutants suggest that members of the GDF family play a key role in establishing boundaries between many different skeletal elements during normal development. Some of the skeletal defects seen in single or double mutant mice resemble defects seen in human skeletal diseases, which suggests that these genes may be candidates that underlie some forms of carpal/tarsal coalition, conductive deafness, scoliosis, and craniosynostosis.