Academic literature on the topic 'Muscular dystrophy x-linked (mdx)'

X-linked muscular dystrophy is a highly progressive disease of childhood and characterized by primary genetic abnormalities in the dystrophin gene. Senescent mdx specimens were used for a large-scale survey of potential age-related alterations in the dystrophic phenotype, because the established mdx animal model of dystrophinopathy exhibits progressive deterioration of muscle tissue with age. Since the mdxtibialis anteriormuscle is a frequently used model system in muscular dystrophy research, we employed this particular muscle to determine global changes in the dystrophic skeletal muscle proteome. The comparison of mdx mice aged 8 weeks versus 22 months by mass-spectrometry-based proteomics revealed altered expression levels in 8 distinct protein species. Increased levels were shown for carbonic anhydrase, aldolase, and electron transferring flavoprotein, while the expressions of pyruvate kinase, myosin, tropomyosin, and the small heat shock protein Hsp27 were found to be reduced in aged muscle. Immunoblotting confirmed age-dependent changes in the density of key muscle proteins in mdx muscle. Thus, segmental necrosis in mdxtibialis anteriormuscle appears to trigger age-related protein perturbations due to dystrophin deficiency. The identification of novel indicators of progressive muscular dystrophy might be useful for the establishment of a muscle subtype-specific biomarker signature of dystrophinopathy.

Abstract Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness because of the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum, but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. The administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for 7 weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.

With the discovery of the X-linked gene product dystrophin, the mdx mouse came to be regarded as the only suitable mouse model of human muscular dystrophy. However, existence of an autosomal gene homologous with dystrophin, together with physiological evidence of membrane fragility, reestablishes autosomal mouse mutants (dy, dy2j) as valid models.

Duchenne muscular dystrophy (DMD) is a musculoskeletal disorder that causes severe morbidity and reduced lifespan. Individuals with DMD have an X-linked mutation that impairs their ability to produce functional dystrophin protein in muscle. No cure exists for this disease and the few therapies that are available do not dramatically delay disease progression. Thus, there is a need to better understand the mechanisms underlying DMD which may ultimately lead to improved treatment options. The muscular dystrophy (MDX) mouse model is frequently used to explore DMD disease traits. Though some studies of metabolism in dystrophic mice exist, few have characterized metabolic profiles of supporting cells in the diseased environment. Using nontargeted metabolomics we characterized metabolic alterations in muscle satellite cells (SCs) and serum of MDX mice. Additionally, live-cell imaging revealed MDX-derived adipose progenitor cell (APC) defects. Finally, metabolomic studies revealed a striking elevation of acylcarnitines in MDX APCs, which we show can inhibit APC proliferation. Together, these studies highlight widespread metabolic alterations in multiple progenitor cell types and serum from MDX mice and implicate dystrophy-associated metabolite imbalances in APCs as a potential contributor to adipose tissue disequilibrium in DMD.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which dystrophin gene is mutated, resulting in dysfunctional or absent dystrophin protein. The pathology of dystrophic muscle includes degeneration, necrosis with inflammatory cell invasion, regeneration, and fibrous and fatty changes. Nevertheless, the mechanisms by which the absence of dystrophin leads to muscle degeneration remain to be fully elucidated. An imbalance between oxidant and antioxidant systems has been proposed as a secondary effect of DMD. However, the significance and precise extent of the perturbation in redox signaling cascades is poorly understood. We report that mdx dystrophic mice are able to activate a compensatory antioxidant response at the presymptomatic stage of the disease. In contrast, increased circulating levels of IL-6 perturb the redox signaling cascade, even prior to the necrotic stage, leading to severe features and progressive nature of muscular dystrophy.

Although Duchenne muscular dystrophy is primarily classified as a neuromuscular disease, cardiac complications play an important role in the course of this X-linked inherited disorder. The pathobiochemical steps causing a progressive decline in the dystrophic heart are not well understood. We therefore carried out a fluorescence difference in-gel electrophoretic analysis of 9-month-old dystrophin-deficient versus age-matched normal heart, using the established MDX mouse model of muscular dystrophy-related cardiomyopathy. Out of 2,509 detectable protein spots, 79 2D-spots showed a drastic differential expression pattern, with the concentration of 3 proteins being increased, including nucleoside diphosphate kinase and lamin-A/C, and of 26 protein species being decreased, including ATP synthase, fatty acid binding-protein, isocitrate dehydrogenase, NADH dehydrogenase, porin, peroxiredoxin, adenylate kinase, tropomyosin, actin, and myosin light chains. Hence, the lack of cardiac dystrophin appears to trigger a generally perturbed protein expression pattern in the MDX heart, affecting especially energy metabolism and contractile proteins.

Patients with Duchenne muscular dystrophy (DMD), an X-linked lethal muscle-wasting disease, have abnormal expression of the protein dystrophin within their muscle fibres. In the mdx mouse model of this condition, both germline and neonatal somatic gene transfers of dystrophin cDNAs have demonstrated the potential of gene therapy in treating DMD. However, in many DMD patients, there appears to be no dystrophin expression when muscle biopsies are immunostained or western blots are performed. This raises the possibility that the expression of dystrophin following gene transfer might trigger a destructive immune response against this ‘neoantigen’. Immune responses can also be generated against the gene transfer vector used to transfect the dystrophic muscle, and the combined immune response could further damage the already inflamed muscle. These problems are now beginning to be investigated in immunocompetent mdx mice. Although much work remains to be done, there are promising indications that these immune responses might not prove as much of a concern as originally envisaged.

Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder in children, is an X-linked recessive muscle disease characterized by the absence of dystrophin at the sarcolemma of muscle fibers. We examined a putative endometrial progenitor obtained from endometrial tissue samples to determine whether these cells repair muscular degeneration in a murine mdx model of DMD. Implanted cells conferred human dystrophin in degenerated muscle of immunodeficient mdx mice. We then examined menstrual blood–derived cells to determine whether primarily cultured nontransformed cells also repair dystrophied muscle. In vivo transfer of menstrual blood–derived cells into dystrophic muscles of immunodeficient mdx mice restored sarcolemmal expression of dystrophin. Labeling of implanted cells with enhanced green fluorescent protein and differential staining of human and murine nuclei suggest that human dystrophin expression is due to cell fusion between host myocytes and implanted cells. In vitro analysis revealed that endometrial progenitor cells and menstrual blood–derived cells can efficiently transdifferentiate into myoblasts/myocytes, fuse to C2C12 murine myoblasts by in vitro coculturing, and start to express dystrophin after fusion. These results demonstrate that the endometrial progenitor cells and menstrual blood–derived cells can transfer dystrophin into dystrophied myocytes through cell fusion and transdifferentiation in vitro and in vivo.

The mdx mouse is widely used as a model for Duchenne Muscular Dystrophy, a fatal X-linked disease caused by a deficiency of the sub-sarcolemmal protein, dystrophin. This dissertation reports characterisation of the features of dystrophy in the mdx mouse, including parameters such as electrophysiological and contractile properties of dystrophic cardiac tissue, quantitative evaluation of kyphosis throughout the mdx lifespan, and contractile properties of respiratory and paraspinal muscles. Following these characterisation studies, the efficacy of antisense oligonucleotides (AOs) to induce alternative mRNA splicing in mdx skeletal muscles (diaphragm and paraspinal muscles) was evaluated. The left atria of younger (<6 weeks) and older (>15 months) mdx mice showed consistently lower basal forces and responsiveness to increased calcium, while action potential duration was significantly shorter in young mice (3 weeks) and older mice (9 and 12 months) (P<0.05). Cardiac fibrosis increased with age in mdx atria and ventricles and was elevated in young (6-8 weeks) and old (15 months) mdx compared to control mice (P<0.01). This study provided insights into DMD cardiomyopathy, and suggested that very young or old mdx mice provide the most useful models. Mdx mice show thoracolumbar kyphosis like boys with Duchenne Muscular Dystrophy. A novel radiographic index, the Kyphotic Index (KI), was developed and showed that mdx mice are significantly more kyphotic from 9 months of age, an effect maintained until 17 months (P<0.05). At 17 months, the paraspinal and respiratory muscles (latissimus dorsi, diaphragm and intercostal muscles) are significantly weaker and more fibrotic (P<0.05). Administration of AOs at four sites within the diaphragm at 4 and 5 months of age significantly increased twitch and tetanic forces compared to sham treated mdx (P<0.05). However, no difference in collagen was evident and dystrophin was not detected, possibly due to the low concentration of AO utilised. This study suggested that AOs can provide functional improvement in treated skeletal muscles. Monthly injections with AOs into the paraspinal muscles from 2 months to 18 months of age alleviated kyphosis, without significantly altering twitch and tetanic forces of latissimus dorsi, diaphragm and intercostal muscles. There was evidence of less fibrosis in diaphragm and latissimus dorsi muscles (P<0.05) and reduced central nucleation of the latissimus dorsi and intercostal muscles (P<0.05). Again, dystrophin was not detected by immunoblot. These studies indicate that very young and old mdx mice display previously uncharacterised dystrophic features, and are useful models for testing new therapies such as AOs. Low doses of AOs were shown to be safe and efficacious for long-term use, however there remains a need for testing higher concentrations and improved delivery strategies.

The dystrophinopathies are a group of disorders characterised by cellular absence of the membrane stabilising protein, dystrophin. Duchenne muscular dystrophy is the most severe disorder clinically. The deficiency of dystrophin, in the muscular dystrophy X-linked (mdx) mouse causes an elevation in intracellular calcium in cardiac myocytes. Potential mechanisms contributing to increased calcium include enhanced influx, sarcoplasmic reticular calcium release and\or reduced sequestration or sarcolemmal efflux. This dissertation examined the potential mechanisms that may contribute to an intracellular calcium overload in a murine model of muscular dystrophy. The general cardiomyopathy of the mdx myocardium was evident, with the left atria from mdx consistently producing less force than control atria. This was associated with delayed relaxation. The role of the L-type calcium channels mediating influx was initially investigated. Dihydropyridines had a lower potency in contracting left atria corresponding to a redued dihydropyridine receptor affinity in radioligand binding studies of mdx ventricular homogenates (P<0.05). This was associated with increased ventricular dihydropyridine receptor protein and mRNA levels (P<0.05). The function of the sarcoplasmic reticulum in terms of release and also sequestration of calcium via the sarco-endoplasmic reticulum ATPase were investigated. A lower force of contraction was evident in mdx left atria in response to a range of stimulation frequencies (P<0.05) and concentrations of extracellular calcium (P<0.05). However, in the presence of 1 nM Ryanodine to block sarcoplasmic reticular calcium release, increased stimulation frequency caused similar forces to those obtained in control mice suggesting enhanced calcium influx via L-type calcium channels in mdx. Rapid cooling contractures showed a reduced contracture in mdx compared to control in response to cooling. This suggests some dysfunction in SR storage, which may be associated with the delayed relaxation time. Concentration-response curves to inhibitors of the sarco-endoplasmic reticulum showed no difference in function of the enzyme responsible for calcium uptake into the sarcoplasmic reticulum. Although sarco-endoplasmic reticulum ATPase mRNA was upregulated, no functional benefit was evident. This study indicates that a deficiency of dystrophin leads to upregulation of L-type calcium channels that contribute to increased calcium influx, with no functional change in sarcoplasmic reticular sequestration. Upregulation of the influx pathway is a potential mechanism for the calcium overload observed in mdx cardiac muscle.

Duchenne Muscular Dystrophy (DMD) is a fatal condition occurring in approximately 1 in 3500 male births and is due to the lack of a protein called dystrophin. Initially DMD was considered a skeletal myopathy, but the pathology and consequences of cardiomyopathy are being increasingly recognised. Fibrosis, resulting from continual cycles of degeneration of the muscle tissues followed by inadequate regeneration of the muscles, is progressive in both cardiac and skeletal dystrophic muscle. In the heart fibrosis interferes with contractility and rhythm whereas it affects contractile function and causes contractures in skeletal muscles. This study utilised the mdx mouse which exhibits a pathological loss of muscle fibres and fibrosis characteristic of DMD, to examine a range of mechanisms that can influence muscle function and fibrosis. Ageing and workload both appear to contribute to the development of dystrophic features in cardiac and skeletal muscle of the mdx mouse. Therefore the effect of eccentric exercise on cardiac and skeletal muscle was examined in older mdx mice. Mice ran in 30 minute sessions for five months, 5 days per week. Downhill treadmill running did not exacerbate the contractile function or fibrosis of the mdx heart or the EDL, SOL or diaphragm muscles suggesting that cytokines influence function and fibrosis to a greater extent than workload alone. The role of the cytokine TGF-beta was examined by treating mdx mice with the TGF-beta antagonist pirfenidone at 0.4, 0.8 or 1.2 per cent in drinking water for six months. Pirfenidone improved cardiac contractility (P<0.01) and coronary flow (P<0.05), to levels comparable to control mice, despite no reduction in cardiac fibrosis. Pirfenidone did not reduce fibrosis or improve function in skeletal muscle. A deficiency of neuronal nitric oxide synthase (nNOS) in DMD and mdx mice causes a lowered production of nitric oxide indicating that the substrate of nNOS, l-arginine, may be beneficial to cardiac and skeletal muscle function in mdx mice. Oral l-arginine (5 mg/g bw) improved cardiac contractility, coronary flow and reduced cardiac fibrosis (P<0.05) without improving skeletal muscle function or fibrosis. In contrast, 10 mg/g bw l-arginine improved cardiac function and coronary flow (P<0.01), despite also elevating cardiac collagen. This increment in collagen was prevented by co-administration of prednisone. The experiments described in this dissertation reveal for the first time that pharmacological treatments in mdx mice can improve cardiac structure and function. Further elucidation of the optimum time and doses of such treatments may result in future pharmacological treatments to improve cardiac function and fibrosis in DMD.

La dystrophie musculaire de Duchenne (DMD) est une dystrophie musculaire fatale de l'enfant, due à l'absence de dystrophine, protéine du cytosquelette des myofibres. Dans le modèle murin mdx de la DMD, les lésions musculaires d'anisocytose, conversion oxydative des fibres, nécrose et régénération peuvent être quantifiées par analyse de texture en IRM, méthode non invasive proposée pour le suivi d'essais thérapeutiques entrepris dans ce modèle. Dans le modèle canin GRMD, la forme néonatale fulminante est un modèle des lésions précoces de dystrophinopathie, et la forme classique observée à partir de l'âge de deux mois un excellent modèle lésionnel de la DMD. Le réseau capillaire du muscle GRMD est quantitativement peu modifié par rapport aux témoins. La structure des capillaires est modifiée par duplication de la membrane basale qui, avec la fibrose endomysiale précoce, représente un obstacle physique à la diffusion d'un produit thérapeutique génique ou cellulaire.

Orientador: Maria Julia Marques
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-21T09:08:14Z (GMT). No. of bitstreams: 1 Apolinario_LeticiaMontanholi_M.pdf: 1840325 bytes, checksum: aac9928181ab48946d6ed91bfa3a9c50 (MD5) Previous issue date: 2012
Resumo: A Distrofia Muscular de Duchenne (DMD) é uma doença recessiva ligada ao cromossomo X. Os glicocorticoides são amplamente utilizados para o tratamento da DMD, entretanto os efeitos colaterais decorrente de seu uso contínuo motivam a busca por novas terapias farmacológicas. Ácidos graxos poli-insaturados têm sido empregados para o tratamento de várias doenças, exercendo seus efeitos através de mecanismos pouco conhecidos... O resumo, na íntegra, poderá ser visualizado no texto completo da tese digital
Abstract: Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disease that leads to myonecrosis and cardiorespiratory failure. Glucocorticoids are so far the choice treatment for DMD. However their side effects due to continuous use motivate the search for new therapies¿ The complete Abstract is available with the full electronic document
Mestrado
Anatomia
Mestra em Biologia Celular e Estrutural

The nuclear matrix (NM) is proposed to be a permanent network of core filaments underlying thicker fibres, present regardless of transcriptional activity. It is found to be both RNA and protein rich; indeed, numerous important nuclear proteins are components of the structure. In addition to mediating the organisation of entire chromosomes, the NM has also been demonstrated to tether telomeres via their TTAGGG repeats. In order to examine telomeric interactions with the NM, a technique known as the DNA halo preparation has been employed. Regions of DNA that are tightly attached to the structure are found within a so-called residual nucleus, while those sequences forming lesser associations produce a halo of DNA. Coupled with various FISH methodologies, this technique allowed the anchorage of genomic regions by the NM, to be analysed. In normal fibroblasts, the majority of chromosomes and telomeres were extensively anchored to the NM. Such interactions did not vary significantly in proliferating and senescent nuclei. However, a decrease in NM-associated telomeres was detected in quiescence. Since lamin A is an integral component of the NM, it seemed pertinent to examine chromosome and telomere NM-anchorage in Hutchinson-Gilford Progeria Syndrome (HGPS) fibroblasts, which contain mutant forms of lamin A. Indeed, genome tethering by the NM was perturbed in HGPS. In immortalised HGPS fibroblasts, this disrupted anchorage appeared to be rescued; the implications of this finding will be discussed. This study also suggested that telomere-NM interactions are aberrant in X-linked Emery-Dreifuss Muscular Dystrophy (X-EDMD), which is caused by mutant forms of emerin, another NM-associated protein. The positioning of selected genes in control and X-EDMD cell lines was examined in un-extracted nuclei using 2D and 3D FISH. Subtle shifts in the organisation of these genes were detected in diseased cells; however, their expression levels remained unaltered. Furthermore, in order to examine the architectural integrity of the nuclear lamina in lamin A and emerin mutant cell lines, scanning electron microscopy (SEM) was employed. This work revealed that such structures were indeed compromised in disease. The findings presented in this thesis highlight the importance of lamin A and emerin in mediating the organisation of the genome and taken together, promote the hypothesis that dysfunctional NM dynamics may well contribute to disease pathology.

Duchenne Muscular Dystrophy (DMD) is a severe and progressive skeletal muscle wasting disease characterised by [Ca2+]-induced hyper-catabolism, and subsequently, a higher demand for energy production to modulate intracellular Ca2+ homeostasis, and protein degradation and synthesis pathways. The broad aim of this thesis was to elucidate potential defects in metabolism of the C57BL/10 mdx mouse model of DMD, and to determine the role of Ca2+ in any such defects. In particular, this thesis has examined the efficacy of the nutritional supplements creatine (Cr) and to a lesser extent, isolated whey protein (WP), in improving intracellular Ca2+ regulation, energy and protein balance and tissue architecture, thus alleviating a degree of the dystrophic pathology. 1. Whether the ATP-producing capacity of dystrophic mitochondria is defective remains largely contentious, and no study to date has directly quantified and contrasted ATP-production rate under the major macronutrient pathways feeding the mitochondria in either mdx hind limb or the more human DMD phenotype-like diaphragm. Chapter Three has demonstrated severely depressed mitochondrial ATP production rate (MAPR) of mdx diaphragm across all macronutrient substrate pathways, but to a lesser extent under protein metabolism, and in tibialis anterior (TA) across the sum of all macronutrient substrate pathways. Function of the electron transport chain complex II was not impaired in dystrophic diaphragm, but was notably depressed in TA. Citrate synthase activity was comparable to controls in both muscles, as was mitochondrial protein content. However, the susceptibility of dystrophic mitochondrial to mechanical damage during the mitochondria isolation process was significantly greater in mdx compared to controls, and in diaphragm compared to TA. It is postulated that mdx skeletal muscle has an intrinsic inability to utilise macronutrient substrates leading to substrate “back-up” and inhibition/down-regulation of key Krebs’ cycle enzymes, thus creating an intracellular “starvation” scenario. That protein metabolism was less affected than the other macronutrient substrate pathways suggests that a portion of the muscle hyper-catabolism observed in DMD may occur due to autophagy to increase amino acid funnelling to mitochondria for ATP production. 2. Supplementation of the high-energy storage nutrient Cr is demonstrably beneficial in maintaining muscle function, energy status and cell survival rate in human DMD and dystrophic mdx skeletal muscle. Long-term chronic dose supplementation regimes, however, have been associated with down-regulation of creatine transporter (CreaT) expression thus making such regimes futile in maintaining consistently high intramuscular PCr stores. Chapter Four has demonstrated successful prevention of CreaT mRNA down-regulation by a chronic dose in utero and life-long Cr supplementation protocol, and subsequently persistently elevated [PCr] compared to unsupplemented mdx skeletal muscle. This was associated with a drastically reduced amount of muscle damage as depicted by Evan’s blue dye (EBD) uptake into myofibres, and a lesser degree of damage to those fibres that were permeant to EBD. This unequivocally demonstrates that muscle wasting occurs secondary to metabolic compromise and failure to maintain ATP supply to intracellular mechanisms that promote cell survival. 3. Effective intracellular Ca2+ regulation by the sarcoplasmic reticulum (SR) is integral to muscle function and becomes of paramount importance to the maintenance of cell survival in conditions of increasing [Ca2+]i such as that evident in DMD. Chapter Five details an optimised method for the fluorometric quantitation of SR Ca2+ flux kinetics currently utilised by our laboratory. It was demonstrated that the SR Ca2+ ATPase (SERCA) preferentially utilises ATP produced by a linked creatine kinase (CK) system over both exogenously administered ATP and ATP produced by SR-linked glycolytic enzymes, and as such, SR Ca2+ uptake rate was considerably faster under these conditions. It was also demonstrated that high [ADP] proximal to the SR vesicles impairs the binding of Ca2+ to Fura-2 and that the presence of 25mM PCr and low [ADP] drastically reduces passive Ca2+ leak from the SR. Thus, this study provides sound rationale for the use of Cr supplementation to improve intracellular Ca2+ handling by the SR subsequent to increasing PCr stores and the buffering of rising [ADP] during metabolic compromise. 4. It has been suggested that the beneficial effects observed in human DMD and dystrophic mdx skeletal muscle following Cr supplementation result from an improved capacity for intracellular Ca2+ handling by the SR and, therefore, delayed degenerative progression. Chapter Six has demonstrated no direct modulatory effect for Cr supplementation on SERCA or RyR function such to increase/decrease SR Ca2+ uptake, leak or release rates, but postulates that the benefit imparted by Cr supplementation is in maintaining maximum uptake (and subsequently release) velocity secondary to buffering rising [ADP] and collapse of the ATP:ADP ratio proximal to the SR. This study has also investigated the effects of supplementation with WP and a Cr+WP combination. As with Cr supplementation, WP induced no direct modulation of SR Ca2+ flux kinetics. Both supplements were shown to modulate differential expression of specific intracellular protein pools, although not necessarily net protein accretion. It is speculated that modification of expressed intracellular protein pools permits the “switching” of dystrophic mdx skeletal muscle from a “functional” phenotype to a “cell survival” phenotype, and that this is inhibited in unsupplemented muscle by a lack of amino acid and energy resources. It was also apparent that Cr and WP supplementation exerted different effects on tissue architecture maintenance. Cr supplementation increased the proportional area of functional muscle tissue and decreased non-muscle “gap” areas thus suggesting a role in muscle hypertrophy, where as Cr+WP combined increased active/recent degeneration and regeneration and the proportion of centrally-nucleated previously damaged fibres compared to peripherally-nucleated undamaged fibres in functional muscle tissue, thus indicating a potentially damaging effect. Collectively, the studies comprising this thesis indicate that the progressive skeletal muscle wasting evident in DMD is closely related to dissipating energy stores, and that the primary disease pathology may, therefore, be an intrinsic metabolic defect caused by the DMD genotype that subsequently induces Ca2+ dys-regulation. Cr supplementation was shown to provide several benefits to dystrophic mdx skeletal muscle architecture, including reduced severity of degenerative cycles, maintenance of muscle tissue and reduced proportional area of non-muscle tissue secondary to increased intramuscular [PCr]. The findings of Chapter Five suggest that Cr supplementation modulates its effect by maintaining normal [PCr] and a high ATP:ADP and PCr:Cr proximal to the SR, such to maintain maximum Ca2+ uptake velocity and reduce passive Ca2+ leak. Both Cr and WP supplementation also seem to modulate intracellular protein synthesis such to increase the capacity for myofibre survival. Thus, these supplements could be of benefit in the adjunct treatment of DMD, and warrant further investigation as to their long-term and mechanistic efficacy.

Duchenne’s muscular dystrophy (DMD) is a progressive X-linked recessive disorder that affects boys and female carriers. It is the most common dystrophy with onset in childhood in the United States. It is associated with severe, progressive proximal muscle weakening due to absence of dystrophin, which is found in skeletal and cardiac muscles This chapter presents a review of anesthetic considerations for patients with DMD in the context of the disease’s natural history with special consideration for cardiomyopathy evaluation and management, restrictive lung disease evaluation, and management and postoperative ventilation. The chapter covers an overview of the disease; etiology and pathogenesis; cognitive, neuromuscular, cardiac, and pulmonary clinical presentation; diagnosis and management; and special anesthetic considerations.

Duchenne muscular dystrophy (DMD) is one of the fatal X-linked disorders that are characterized by progressive muscle weakness and occur due to mutation in the largest human gene known as the DMD gene which encodes dystrophin protein that is mandatory for keeping the muscles structurally and functionally intact. The disease always affects boys (1 from every ~5000), and in some cases the female carriers are symptomatic. The disease usually leads to impairment in cardiac and pulmonary functions leading to the death of the patients in very young ages. Understanding DMD through precise molecular diagnosis will aid in determining the suitable therapeutic approach for the cases like designing exon-skipping antisense oligonucleotides (AOs) or stem cell-based therapies in conjunction with gene editing techniques (CRISPR/Cas9). Such therapies can correct the genetic defect in the DMD gene and ameliorate the symptoms. In this chapter, we will illustrate the past and current strategies for DMD disease treatment.

The dystrophinopathies, including Duchenne and Becker muscular dystrophies, are X-linked, developmental neuromuscular disorders. The dystrophinopathies are so named because of their effect on the production of the protein dystrophin, and are known primarily as muscle diseases in males that present with progressive weakness that is eventually fatal. To date, there is no cure for the dystrophinopathies, and treatment focuses on slowing the disease progression. Medical management is complex and multifaceted. It includes care for neuromuscular, orthopedic, rehabilitative, nutritional, respiratory, cardiac, gastrointestinal, psychological, and palliative aspects of the disease. The devastating physical toll of the diseases is well known. In contrast, the associated cognitive and behavioral abnormalities are less familiar to most clinicians. Nonetheless, the cognitive and behavioral attributes of the dystrophinopathies impact on the affected individual’s and his family’s functioning in far-ranging ways. More importantly, identifying any associated cognitive and behavioral abnormalities early, and providing appropriate interventions, can contribute substantially to an affected individual’s quality of life. The dystrophinopathies are the most common neuromuscular diseases of childhood, affect all ethnic groups, and have an estimated overall prevalence of 63 per million (Emery 1991; Emery 1992). Positive diagnosis for the Duchenne muscular dystrophy (DMD, the more severe form) is based on the following criteria: (a) male; (b) onset of weakness before age 5; (c) initial proximal muscle weakness; (d) muscle hypertrophy, most prominent in the calves; (e) elevated creatine kinase activity of at least 10 times above the upper limit of normal; and either (f) positive histopathological confirmation by muscle biopsy or (g) molecular characterization of a mutation within the gene for dystrophin. Approximately 1 in 3,500 live male births meet these criteria (Emery 1992). The diagnosis of Becker muscular dystrophy (BMD, the less severe form) is clinically determined by those children who remain walking at age 12. Individuals with BMD have a slower course and considerably longer lifespan than those with DMD. Natural history studies have been conducted to characterize the course of the disease. The Clinical Investigation of Duchenne Dystrophy group (CIDD) followed more than 200 individuals affected with DMD for more than 10 years (Brooke et al. 1983; Hyser et al. 1987; Mendell et al. 1987).