Muscle Function In Children Research Articles

Paper #21: Serial Measures of Lung and Inspiratory Muscle Function in Children With Early-Onset Scoliosis

change in diaphragm volume less than convex, 1 had concave greater than convex, and 2 had equal volumes. For 3 patients with postoperative scans, concave change in rib cage volume increased 57% (convex, 72%) and change in diaphragm volume increased 128% (convex, 109%). Concave kidney excursion increased 6.3 mm (320%), and convex 5.2 mm (192%). Complications included 2 patients with migration of devices proximally. Conclusions: Quantitative dMRI can measure separate contributions of diaphragm and rib cage to lung expansion during respiration for each hemithorax, enabling accurate assessment of thoracic function for the first time. Vertical Expandable Prosthetic Titanium Rib treatment appears to increase rib cage expansion more on the convex side of the thorax than the concave, and conversely increases diaphragm excursion on the concave side. With treatment, renal excursion increases bilaterally, concave more than convex, probably reducing a blockade effect on the diaphragm. Quantitative dMRI has the potential to increase understanding of the anatomic mechanisms of spine/chest wall deformity that cause restrictive lung disease in NM scoliosis, and may enable the development of new treatments for it.

Spinal muscular atrophy: therapeutic strategies.

Spinal muscular atrophy is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The loss of alpha motor neurons in the ventral horn of the spinal cord results in progressive paralysis and premature death. There is no current treatment other than symptomatic and supportive care, although over the past decade, there has been an outstanding advancement in understanding the genetics and molecular mechanisms underlying the physiopathology of SMA. The most promising approach, from current trials, is the use of antisense oligonucleotide (ASOs) to redirect SMN2 translation and increase exon 7 inclusion in the majority of the RNA transcript, to increase the production of fully functional SMN protein. Recently, ISIS Pharmaceuticals Inc. (2855 Gazelle Court, Carlsbad CA 92010) reported an interim analysis from a multiple dose study in children with SMA between 2 and 14 years of age, using ASO therapy. The results indicated good tolerability at all dose levels, increases in muscle function in children treated with multiple doses of ISIS-SMNRx, and increase in SMN protein levels in cerebrospinal fluid (CSF) from both single and multiple dose studies. Studies in infants are ongoing in a few centers; soon other institutions may begin enrollment. Infants are fragile and their disease process may differ from the older SMA population. It is not known whether effective drug would best be given to SMA infants or older children. Other promising therapies are still in preclinical phases or early clinical phases. Gene therapy appears to be efficient in improving survival in a severe mouse model of SMA, though a better definition of the route of administration and of the safety profile of the viral vectors is needed before clinical administration is possible.

Fitness and physical activity in youth with type 1 diabetes mellitus in good or poor glycemic control

Patients with type 1 diabetes mellitus (T1DM) may experience poor muscle health as a result of chronic hyperglycemia. Despite this, muscle function in children with T1DM with good or poor glycemic control has yet to be examined in detail. To assess differences in muscle-related fitness variables in children with T1DM with good glycemic control (T1DM-G), as well as those with poor glycemic control (T1DM-P), and non-diabetic, healthy controls. Eight children with T1DM-G [glycosylated hemoglobin (HbA1c) ≤ 7.5% for 9 months], eight children with T1DM-P (HbA1c ≥ 9.0% for 9 months), and eight healthy controls completed one exercise session. Anaerobic and aerobic muscle functions were assessed with a maximal isometric grip strength test, a Wingate test, and an incremental continuous cycling test until exhaustion. Blood samples were collected at rest to determine HbA1c at the time of testing. Physical activity was monitored over 7 d using accelerometry. Children with T1DM-P displayed lower peak oxygen consumption (VO2peak ) values (mL/kg/min) compared to healthy controls (T1DM-P: 33.2 ± 5.6, controls: 43.5 ± 6.3, p < 0.01), while T1DM-G (43.5 ± 6.3) had values similar to controls and T1DM-P. There was a negative relationship between VO2peak and HbA1c% (r = -0.54, p < 0.01). All groups were similar in all other fitness variables. There were no group differences in physical activity variables. Children with T1DM-G did not display signs of impaired muscle function, while children with T1DM-P have signs of altered aerobic muscle capacity.

NF1 is a critical regulator of muscle development and metabolism

There is emerging evidence for reduced muscle function in children with neurofibromatosis type 1 (NF1). We have examined three murine models featuring NF1 deficiency in muscle to study the effect on muscle function as well as any underlying pathophysiology. The Nf1(+/-) mouse exhibited no differences in overall weight, lean tissue mass, fiber size, muscle weakness as measured by grip strength or muscle atrophy-recovery with limb disuse, although this model lacks many other characteristic features of the human disease. Next, muscle-specific knockout mice (Nf1muscle(-/-)) were generated and they exhibited a failure to thrive leading to neonatal lethality. Intramyocellular lipid accumulations were observed by electron microscopy and Oil Red O staining. More mature muscle specimens lacking Nf1 expression taken from the limb-specific Nf1Prx1(-/-) conditional knockout line showed a 10-fold increase in muscle triglyceride content. Enzyme assays revealed a significant increase in the activities of oxidative metabolism enzymes in the Nf1Prx1(-/-) mice. Western analyses showed increases in the expression of fatty acid synthase and the hormone leptin, as well as decreased expression of a number of fatty acid transporters in this mouse line. These data support the hypothesis that NF1 is essential for normal muscle function and survival and are the first to suggest a direct link between NF1 and mitochondrial fatty acid metabolism.

The Effect of Whole Body Vibration Exposure on Muscle Function in Children With Cystic Fibrosis: A Pilot Efficacy Trial

BackgroundTo examine the effects of whole body vibration (WBV) exposure on muscle function in children with Cystic Fibrosis (CF). Non-randomised controlled cross-over trial.MethodsThe setting was home-based WBV exposure. The participants were children (8 - 15 years) with CF (n = 7). Intervention: participants served as their own controls for the first four weeks (usual care), then underwent four weeks of parentally-supervised home-based WBV exposure followed by four weeks washout (usual care). The WBV exposure consisted of 20 - 30 minutes of intermittent (1 min vibration:1 min rest) exposure on a Galileo platform (20 - 22Hz, 1 mm amplitude) 3 days/week. The primary outcome measures of absolute and relative lower body (leg extension (LE), leg press (LP)), upper body (chess press (CP)) strength and power, and power were measured at baseline, and weeks 4, 8 and 12. Secondary exploratory outcomes were cardiorespiratory fitness, pulmonary function and health-related quality of life.ResultsSix participants completed the training without adverse events. Muscle function changes following WBV exposure were not statistically significant. However, moderate-to-large relative effect sizes (ES) favouring WBV were evident for leg extension strength (ES = 0.66 (-0.50, 1.82)), LP relative strength (ES = 0.92 (-0.27, 2.11)), leg press peak power (ES = 0.78 (-0.50, 2.07)) and CMJ height (ES = 0.60 (-0.56 to 1.76)).ConclusionsThe results from this first controlled trial indicate that WBV may be a potentially effective exercise modality to safely increase leg strength and explosive power in children with CF. Potentially clinically relevant changes support continued investigation of the efficacy, mechanism and feasibility of this intervention in future large-scale studies.

Vitamin D: an overview of its role in skeletal muscle physiology in children and adolescents

Many children may have insufficient serum concentrations of vitamin D, which could prevent optimal muscle development and function. Vitamin D deficiency in animal models results in negative effects on muscle fiber structure and calcium/phosphorus handling, suggesting an integral role of vitamin D in skeletal muscle function. While there is a dearth of data in humans, the available evidence demonstrates a positive association between vitamin D status and muscle function. This review focuses on the important role of vitamin D in muscle function in children and adolescents who live in North American regions where exposure to ultraviolet B radiation is limited and who are thus at increased risk for vitamin D insufficiency. The effects of vitamin D on muscle cell proliferation and differentiation, muscle fiber structure, and calcium and phosphorus handling are discussed. Moreover, the roles of vitamin D and the vitamin D receptor and their genomic and nongenomic actions in muscle function are explored in depth. Future research should aim to establish a vitamin D status consistent with optimal musculoskeletal development and function in young children.

A mass–length scaling law for modeling muscle strength in the lower limb

Musculoskeletal computer models are often used to study muscle function in children with and without impaired mobility. Calculations of muscle forces depend in part on the assumed strength of each muscle, represented by the peak isometric force parameter, which is usually based on measurements obtained from cadavers of adult donors. The aim of the present study was twofold: first, to develop a method for scaling lower-limb peak isometric muscle forces in typically-developing children; and second, to determine the effect of this scaling method on model calculations of muscle forces obtained for normal gait. Muscle volumes were determined from magnetic resonance (MR) images obtained from ten children aged from 7 to 13 yr. A new mass–length scaling law was developed based on the assumption that muscle volume and body mass are linearly related, which was confirmed by the obtained volume and body mass data. Two musculoskeletal models were developed for each subject: one in which peak isometric muscle forces were estimated using the mass–length scaling law; and another in which these parameters were determined directly from the MR-derived muscle volumes. Musculoskeletal modeling and quantitative gait analysis were then used to calculate lower-limb muscle forces in normal walking. The patterns of muscle forces predicted by the model with scaled peak isometric force values were similar to those predicted by the MR-based model, implying that assessments of muscle function obtained from these two methods are practically equivalent. These results support the use of mass–length scaling in the development of subject-specific musculoskeletal models of children.

Aerobic capacity and skeletal muscle function in children with asthma

BackgroundPeripheral muscle strength and endurance are decreased in patients with chronic pulmonary diseases and seem to contribute to patients' exercise intolerance. However, the authors are not aware of any studies...

Analyses of muscular mass and function: the impact on bone mineral density and peak muscle mass

Bone density and bone mass are commonly regarded as the essential parameters to describe fracture risk in osteology. Because fractures primarily depend on bone strength and secondarily on bone mass and density, bone strength should be the main parameter to describe fracture risk. The quantitative description of bone strength has the prerequisite that bone geometry is assessed despite bone density. Thus, volumetric osteodensitometric methods should be preferred, which enable the physician to evaluate parameters primarily associated with bone modeling or remodeling. Modeling describes the adaptation of bone geometry to applied muscular forces in contrast to remodeling representing bone turnover. The adaptation of bone geometry to muscle forces led to the term functional muscle-bone unit, which enables the physician to differentiate between primary and secondary bone diseases. Primary bone diseases are characterized by a defective adaptation of bone to muscle forces in contrast to secondary bone diseases, which are primary diseases of the neuromuscular system. Because muscle forces are essential in the feedback loop of bone adaptation to forces (mechanostat), the assessment of muscle function has become an essential part of osteologic diagnostics in pediatrics. Dynamometric and mechanographic methods have been introduced to properly characterize kinetic aspects of muscle function in children and adolescents. Therefore, emphasis should be put on the assessment of muscle function despite the evaluation of osteodensitometric parameters in pediatric osteology.

Waist Circumference, Atherogenic Lipoproteins, and Vascular Smooth Muscle Biomarkers in Children

Large waist circumference (WC) is associated with cardiovascular disease and type 2 diabetes. The present study determined differences in lipoprotein particle size and subclass concentration and markers of vascular smooth muscle function in children using WC percentile cutoffs. Participants were 182 children (87 black, 92 female) aged 8-<18 yr. Each participant had a measurement of WC and a fasting blood draw for the measurement of lipoprotein particle concentration and size and circulating biomarkers of endothelial function. Participants were divided into age-, sex-, and ethnicity-specific WC percentiles of below 75th, 75th to 90th, and at least 90th percentiles, and differences in lipoproteins and vascular smooth muscle markers were compared among groups. Children in the 90th percentile or higher for WC had significantly smaller low-density lipoprotein and high-density lipoprotein size than children with WC below this percentile. For lipoprotein concentration, small low-density lipoprotein and large very low density lipoprotein and chylomicrons were lower, and large high density lipoprotein concentrations were higher in children whose WC was below the 75th percentile compared with those with WC in the 90th percentile or higher. Concentrations of the vascular smooth muscle biomarkers, intercellular adhesion molecule-1, and E-selectin were significantly higher in children with WC in the 90th percentile or higher than in children below the 75th percentile. Youths with WC in the 90th percentile or higher have an atherogenic lipoprotein profile with increased concentrations of biomarkers of vascular smooth muscle dysfunction. Given that atherosclerosis begins in childhood, such evidence suggests that these children should be targeted for interventions to reduce adiposity at an early age.

P088 The relation between ataxia and muscle function in children with Friedreich's ataxia

P088 The relation between ataxia and muscle function in children with Friedreich's ataxia

Non‐invasive assessment of exercise performance in children with cystic fibrosis (CF) and non‐cystic fibrosis bronchiectasis: Is there a CF specific muscle defect?

Peripheral muscle dysfunction is increasingly recognized as complicating respiratory disease, but this is difficult to measure non-invasively. Can skeletal muscle function and efficiency be measured during exercise non-invasively using respiratory mass spectrometry (RMS); and is the known exercise dysfunction in cystic fibrosis (CF) children related in part to a disease specific defect of skeletal muscle, or a non-specific manifestation of chronic airway infection and inflammation. Calculations of effective pulmonary blood flow and stroke volume, blood oxygen content and oxygen dispatch from the lungs, skeletal muscle oxygen extraction and consumption, anerobic threshold and capacity, and gross, net and work efficiency in 106 controls and 36 children (18 CF) with bronchiectasis, all aged from 8 to 17 years. Normal values for control subjects are tabulated. CF and non-CF bronchiectatic subjects had similar physiology, and skeletal muscle abnormalities could not be detected. Reduced oxygen dispatch from the lungs, due to an inability to raise stroke volume, without an increase in functional residual capacity was the major factor in reduced exercise ability. Non-invasive RMS can be used to determine skeletal muscle function in children. The changes observed in CF subjects were very similar to non-CF bronchiectatic subjects and thus a CF specific defect was not demonstrated.

Towards harmonisation of outcome measures for DMD and SMA within TREAT-NMD; Report of three expert workshops: TREAT-NMD/ENMC Workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands; TREAT-NMD Workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands; Conjoint Institute of Myology TREAT-NMD Meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007,

Towards harmonisation of outcome measures for DMD and SMA within TREAT-NMD; Report of three expert workshops: TREAT-NMD/ENMC Workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands; TREAT-NMD Workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands; Conjoint Institute of Myology TREAT-NMD Meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007, Paris, France

Non‐invasive tension time index in relation to severity of disease in children with cystic fibrosis

The non-invasive tension-time index of the inspiratory muscles at rest (TTMUS) can be used for assessing respiratory muscle function in children with cystic fibrosis (CF). This study aimed to investigate how TTMUS becomes altered with increasing pulmonary impairment, and which factors determine TTMUS changes in CF. We assessed TTMUS in 47 patients with stable CF ranging in age from 9 to 26 years and in 47 controls of same age and gender. Pulmonary impairment was assessed by the pulmonary function score (PFS) according to Cropp (PFS 0-2 = no, 3-7 = mild, 8-12 = moderate, and 13-18 = severe dysfunction). Median TTMUS was significantly higher in the entire CF-group than in controls ((0.112 (0.079-0.174) vs. 0.07 (0.052-0.094), P < 0.001)). It was nearly identical in CF-patients without (0.079 (0.056-0.114)) and mild (0.080 (0.059-0.128)) pulmonary dysfunction. It was non-significantly higher in subjects with moderate (0.118 (0.103-0.173)) and grossly elevated in individuals with severe (0.232 (0.211-0.31), P < 0.001)) respiratory impairment when compared to the other PFS-groups. TTMUS was significantly related to percent predicted airway resistance (Raw%pred) (r = 0.60, P < 0.001), percent predicted Forced Expiratory Volume in 1 sec (r = -0.49, P < 0.001), percent predicted Vital Capacity (-0.57, P < 0.001), Functional Residual Capacity in percent Total Lung Capacity (r = 0.42, P = 0.003), and transcutaneous oxygen saturation (r = -0.49, P < 0.001). By contrast, Raw%pred was the only variable that had a significant effect on TTMUS (P = 0.01), when a multivariate logistic regression was applied, using the median of the entire CF-cohort to dichotomise TTMUS. These findings suggest that subjects with stable CF and severe pulmonary dysfunction are prone to respiratory muscle fatigue, and that airway obstruction is an important factor contributing to the increase of TTMUS in CF. Regular determination of TTMUS may be clinically useful during course of disease, and may aid the decision to institute therapies like respiratory muscle training or non-invasive intermittent ventilation.

Impaired expression of myogenic regulatory molecules in the pelvic floor muscles of murine embryos with anorectal malformations

Background/Purpose Recent biological studies have elucidated the molecular mechanism of muscle development, in which various regulatory factors (myogenic regulatory factors [MRFs]) play key roles during embryogenesis. To investigate the development of anorectal malformations (ARMs), we studied MRF expressions in myogenic cells in the pelvic floor using murine embryos affected with ARM. Methods Anorectal malformation embryos were obtained from the 10.5th embryonal day (E10.5) to the 7.0th postnatal day (D7.0) in a natural mutant strain (Sd/+, RSV/Le). Serial frozen sections were prepared for immunohistochemistry using specific antibodies to M-cadherin, myoD, Myogenin, myosin heavy chain, and alfa-actin molecule. Results In normal mice, embryonal caudal somites differentiated into myogenic stem cells and migrated to the pelvic floor between E11.0 and E14.0. In the ARM mice, however, caudal somites were irregularly arranged and MRF expressions in myogenic cells were markedly decreased in the dorsocaudal region at E11.5 to E13.0, leading to hypoplastic pelvic floor muscles. Conclusions The maldevelopment of pelvic floor muscles in ARM is derived from a deficient supply of myogenic stem cells, with impaired MRF expression. These results suggest that myogenic stem cells, available from bone marrow contents, may be used for postnatal muscle regeneration to reinforce the pelvic floor muscle function in children with ARM.

Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids 2–4 April 2004, Naarden, The Netherlands

Thirty-two participants representing parents, funding agencies and clinicians involved in the care of children with Duchenne Muscular Dystrophy (DMD) from Belgium, Canada, Denmark, Finland, France, Germany, Italy, the Netherlands, Spain, Sweden, the UK and the USA met in Naarden on 2–4th April 2004. The meeting was held under the auspices of the ENMC Clinical Trials Network, and with the additional support of the United Parent Project. The aims of the workshop were to define the need for clinical trials in DMD and develop a protocol for such trials, relating primarily to the use of steroids (prednisolone, prednisone and deflazacort) in DMD. The first part of the meeting summarised the current state of practice on the use of steroids in DMD. Elizabeth Vroom (Netherlands) and Pat Furlong (USA) presented the views of parents surveyed by questionnaire by the United Parent Project. A major worry for parents was the lack of use of steroids at all in some countries, the multiplicity of steroid regimes used and the problems of getting firm information about which type of steroid or which regime for using steroids was best. This was reflected in the variation in practice amongst the participants at the Workshop, who between them used at least seven different regimes for giving steroids, and some did not use steroids at all. Adnan Manzur (UK), co-author of the Cochrane report on the use of glucocorticosteroids in DMD described the major findings of this systematic review [1]. Only five randomised controlled trials of the use of steroids in DMD were published in sufficient detail to be able to be included in the review. These trials did, however, present evidence that use of daily prednisolone (0.75 mg/kg per day) or deflazacort (0.9 mg/kg per day) increased strength in DMD. Robert Griggs, Richard Moxley (USA) and Doug Biggar (Canada) were able to confirm that long-term follow up of cohorts of patients treated under one or other of these regimes and who mostly continued using steroids beyond the loss of independent ambulation shows that this increase in strength is mirrored by improvement in function (with age at loss of ambulation in the mid teens, preservation of respiratory function, lack of need for scoliosis surgery and possibly preservation of cardiac function) [2–4]. With longterm use of steroids, the per kilogram dose of corticosteroid tended to reduce with time. In some cases, this was in response to side effects such as weight gain or behaviour changes, but in the majority represented a tendency not to keep up strictly with change in weight over time. Many different regimes for giving steroids in DMD have been suggested as a way to reduce the risk of the well-known side effects associated with the long-term use of daily steroids. The dose of 0.75 mg/kg per day was shown to be Neuromuscular Disorders 14 (2004) 526–534 www.elsevier.com/locate/nmd

117th ENMC Workshop: Ventilatory Support in Congenital Neuromuscular Disorders — Congenital Myopathies, Congenital Muscular Dystrophies, Congenital Myotonic Dystrophy and SMA (II) 4–6 April 2003, Naarden, The Netherlands

Eighteen participants from Australia, Austria, Denmark, Finland, France, Germany, The Netherlands, the UK, and the USA met in Naarden, representing a variety of disciplines with experience in the respiratory management of patients with neuromuscular disorders (NMD). The aims of the workshop were to agree upon and report minimum recommendations for the investigation and treatment of respiratory involvement in congenital muscular disorders, and to identify areas where further research is needed. The workshop specifically excluded patients with Duchenne muscular dystrophy where evidence for the need for and efficacy of the treatment of respiratory failure is better established. All participants contributed to the review and assessment of published evidence in the field, and current practice amongst the group was also compared. Despite the individual rarity of the conditions under consideration in this workshop, the accumulated experience of the group represented the care of more than 545 patients with these disorders, of whom around one-third were receiving mechanical ventilation.

Follow-up study of muscle function in children of mothers with myasthenia gravis during pregnancy.

Most infants whose mothers have myasthenia gravis are healthy at birth, but 10% to 15% have a transient neonatal form of myasthenia gravis. In this study, the muscular function and neuromuscular transmission were examined in 31 children, aged 3 months to 31 years (median, 10 years), of 15 myasthenic mothers. Eleven of these children had had the neonatal form of myasthenia gravis. The children were examined clinically and with neurophysiologic methods. Blood samples were taken for HLA typing, creatine kinase levels, and myoglobin and acetylcholine receptor antibody studies. Twenty-nine of the 31 children had no signs of neuromuscular disease. Two children (who had had neonatal myasthenia gravis) had a moderate stationary myopathy, probably unrelated to the myasthenia gravis of their mother. Creatine kinase levels were normal for all subjects. Acetylcholine receptor antibody levels were similar to those of a control population. The HLA type B8 antigen was not significantly more prevalent in the children who had had neonatal myasthenia gravis than in the healthy children. Neonatal myasthenia gravis in a previous sibling was the only factor in the material that predicted the occurrence of myasthenic symptoms in the neonatal period.

Quantitation of muscle function in children: a prospective study in Duchenne muscular dystrophy.

A protocol has been developed for the quantitative assessment of muscle function in children with muscle disease. It includes total muscle strength (% MRC) based on a clinical assessment of strength of 32 groups using the 6-point MRC grading; the force of 8 selected muscle groups measured with a specially designed electromyometer; a motor ability score based on 20 consecutive motor activities; walking times over 28 and 150 feet, and recording of muscle contractures. A 3-year sequential study of 61 boys with Duchenne dystrophy showed progressive decline of muscle strength with age, a close correlation of total strength and the motor ability score (r = 0.89), and a curvilinear relationship of muscle strength with walking times over 28 and 150 feet (r = 0.78 and 0.79, respectively). A profile of the natural progression of Duchenne dystrophy has been established which could serve as a reference base for the assessment of cases at varying ages and their response to therapy and management.

Tests of skeletal muscle function in children.

The contractile properties of a large proximal muscle (quadriceps femoris) and a small distal muscle (adductor pollicis) have been measured in normal children and children with neuromuscular disorders. The method of stimulating the quadriceps femoris to contract, previously evaluated in adults, was found to be acceptable to children. In normal children a number of indices of muscle function were found to be similar to those in adults. A small study of the function of the adductor pollicis using supramaximal stimulation of the ulnar nerve was carried out in boys with Duchenne dystrophy. Decreased contractile force and prolonged relaxation times from a tetanic stimulation were noted in both the proximal and distal muscles of the boys with Duchenne dystrophy.