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Muscle Wasting (muscle + wasting)
Selected AbstractsReduced Nerve Blood Flow In Diabetic Rats Is A Reflection Of Hindlimb Muscle WastingJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 3 2000Dr Tomlinson We examined the influence of muscle wasting, as a result of streptozotocin-induced diabetes, on sciatic nerve laser Doppler flux (SNLDF), as an index of nerve blood flow, and conduction velocity (NCV). We compared dietary-restricted weight-reduced non-diabetic rats with controls and with diabetic rats and we studied the effects of clenbuterol, an anabolic ,-adrenoceptor agonist, in control and diabetic rats. Dietary restriction reduced the weights of hindlimb muscles,extensor digitorum longus, soleus and gastrocnemius,half as much as did streptozotocin-diabetes and clenbuterol increased muscle weights in control and diabetic rats. This gave a hierarchy of muscle weights in the order,clenbuterol-controls, untreated controls, weight-reduced non-diabetics, clenbuterol-diabetics and untreated diabetics. Diabetes without treatment reduced SNLDF by 51% (p < 0.01); dietary restriction by 25% (p < 0.01) and there were proportional increases associated with clenbuterol treatment. Combined muscle weights regressed closely with SNLDF (r2=0.69; p < 0.001) and, when the latter was expressed relative to muscle weights, a similar value was obtained for all five groups,there were no significant differences. Thus, sciatic nerve blood flow is closely related to hindlimb muscle weight and the effect of diabetes on nerve blood flow may be secondary to muscle wasting. Sciatic/tibialis motor and sensory conduction velocities were also reduced by muscle wasting in the dietary restricted group of non-diabetic rats, but, unlike nerve Doppler flux, it was unaffected by clenbuterol. [source] Myotendinous plasticity to ageing and resistance exercise in humansEXPERIMENTAL PHYSIOLOGY, Issue 3 2006N. D. Reeves The age-related loss of muscle mass known as senile sarcopenia is one of the main determinants of frailty in old age. Molecular, cellular, nutritional and hormonal mechanisms are at the basis of sarcopenia and are responsible for a progressive deterioration in skeletal muscle size and function. Both at single-fibre and at whole-muscle level, the loss of force exceeds that predicted by the decrease in muscle size. For single fibres, the loss of intrinsic force is mostly due to a loss in myofibrillar protein content. For whole muscle, in addition to changes in neural drive, alterations in muscle architecture and in tendon mechanical properties, exemplified by a reduction in tendon stiffness, have recently been shown to contribute to this phenomenon. Resistance training can, however, cause substantial gains in muscle mass and strength and provides a protective effect against several of the cellular and molecular changes associated with muscle wasting and weakness. In old age, not only muscles but also tendons are highly responsive to training, since an increase in tendon stiffness has been observed after a period of increased loading. Many of the myotendinous factors characterizing ageing can be at least partly reversed by resistance training. [source] Cardiac ankyrin repeat protein is a marker of skeletal muscle pathological remodellingFEBS JOURNAL, Issue 3 2009Lydie Laure In an attempt to identify potential therapeutic targets for the correction of muscle wasting, the gene expression of several pivotal proteins involved in protein metabolism was investigated in experimental atrophy induced by transient or definitive denervation, as well as in four animal models of muscular dystrophies (deficient for calpain 3, dysferlin, ,-sarcoglycan and dystrophin, respectively). The results showed that: (a) the components of the ubiquitin,proteasome pathway are upregulated during the very early phases of atrophy but do not greatly increase in the muscular dystrophy models; (b) forkhead box protein O1 mRNA expression is augmented in the muscles of a limb girdle muscular dystrophy 2A murine model; and (c) the expression of cardiac ankyrin repeat protein (CARP), a regulator of transcription factors, appears to be persistently upregulated in every condition, suggesting that CARP could be a hub protein participating in common pathological molecular pathway(s). Interestingly, the mRNA level of a cell cycle inhibitor known to be upregulated by CARP in other tissues, p21WAF1/CIP1, is consistently increased whenever CARP is upregulated. CARP overexpression in muscle fibres fails to affect their calibre, indicating that CARP per se cannot initiate atrophy. However, a switch towards fast-twitch fibres is observed, suggesting that CARP plays a role in skeletal muscle plasticity. The observation that p21WAF1/CIP1 is upregulated, put in perspective with the effects of CARP on the fibre type, fits well with the idea that the mechanisms at stake might be required to oppose muscle remodelling in skeletal muscle. [source] Kennedy's disease: pathogenesis and clinical approachesINTERNAL MEDICINE JOURNAL, Issue 5 2004K. J. Greenland Abstract Kennedy's disease, also known as spinal and bulbar muscular atrophy, is a progressive degenerative condition affecting lower motor neurons. It is one of nine neurodegenerative disorders caused by a polyglutamine repeat expansion. Affecting only men, Kennedy's disease is the only one of these conditions that follows an X-linked mode of inheritance. The causative protein in Kennedy's disease, with a polyglutamine expansion residing in the first N-terminal domain, is the androgen receptor. Research in this field has made significant advances in recent years, and with the increased understanding of pathogenic mechanisms, feasible approaches to treatments are being investigated. In Kennedy's disease research, the most significant issue to emerge recently is the role of androgens in exacerbating the disease process. On the basis of animal experiments, a viable hypothesis is that higher circulating levels of androgens in men could trigger the degeneration of motor neurons causing this disease, and that lower levels in heterozygous and homozygous women are protective. This is a major issue, as treatment of individuals affected by Kennedy's disease with testosterone has been considered a reasonable therapy by some neurologists. The rationale behind this approach relates to the fact that Kennedy's disease is accompanied by mild androgen insensitivity. It was therefore believed that treatment with high doses of testosterone might compensate for this loss of androgen action, with the added benefit of preventing muscle wasting. The current review provides an overview of recent advances in the field of Kennedy's disease research, including approaches to treatment. (Intern Med J 2004; 34: 279,286) [source] A concept analysis of malnutrition in the elderlyJOURNAL OF ADVANCED NURSING, Issue 1 2001Cheryl Chia-Hui Chen RN MSN GNP A concept analysis of malnutrition in the elderly Purpose.,Malnutrition is a frequent and serious problem in the elderly. Today there is no doubt that malnutrition contributes significantly to morbidity and mortality in the elderly. Unfortunately, the concept of malnutrition in the elderly is poorly defined. The purpose of this paper is to clarify the meaning of malnutrition in the elderly and to develop the theoretical underpinnings, thereby facilitating communication regarding the phenomenon and enhancing research efforts. Scope, sources used.,Critical review of literature is the approach used to systematically build and develop the theoretical propositions. Conventional search engines such as Medline, PsyINFO, and CINAHL were used. The bibliography of obtained articles was also reviewed and additional articles identified. Key wards used for searching included malnutrition, geriatric nutrition, nutritional status, nutrition assessment, elderly, ageing, and weight loss. Conclusions.,The definition of malnutrition in the elderly is defined as following: faulty or inadequate nutritional status; undernourishment characterized by insufficient dietary intake, poor appetite, muscle wasting and weight loss. In the elderly, malnutrition is an ominous sign. Without intervention, it presents as a downward trajectory leading to poor health and decreased quality of life. Malnutrition in the elderly is a multidimensional concept encompassing physical and psychological elements. It is precipitated by loss, dependency, loneliness and chronic illness and potentially impacts morbidity, mortality and quality of life. [source] Sarcopenia is not due to lack of regenerative drive in senescent skeletal muscleAGING CELL, Issue 2 2005Erik Edström Summary Sarcopenia, loss of skeletal muscle mass, is a hallmark of aging commonly attributed to a decreased capacity to maintain muscle tissue in senescence, yet the mechanism behind the muscle wasting remains unresolved. To address these issues we have explored a rodent model of sarcopenia and age-related sensorimotor impairment, allowing us to discriminate between successfully and unsuccessfully aged cohort members. Immunohistochemistry and staining of cell nuclei revealed that senescent muscle has an increased density of cell nuclei, occurrence of aberrant fibers and fibers expressing embryonic myosin. Using real-time PCR we extend the findings of increased myogenic regulatory factor mRNA to show that very high levels are found in unsuccessfully aged cohort members. This pattern is also reflected in the number of embryonic myosin-positive fibers, which increase with the degree of sarcopenia. In addition, we confirm that there is no local down-regulation of IGF-I and IGF-IR mRNA in aged muscle tissue; on the contrary, the most sarcopenic individuals showed significantly higher local expression of IGF-I mRNA. Combined, our results show that the initial drive to regenerate myofibers is most marked in cases with the most advanced loss of muscle mass, a pattern that may have its origin in differences in the rate of tissue deterioration and/or that regenerating myofibers in these cases fail to mature into functional fibers. Importantly, the genetic background is a determinant of the pace of progression of sarcopenia. [source] Malnutrition, a Rare Form of Child Abuse: Diagnostic CriteriaJOURNAL OF FORENSIC SCIENCES, Issue 3 2006Marie-Dominique Piercecchi-Marti M.D., Ph.D. ABSTRACT: Infantile malnutrition is often difficult to diagnose as it is rarely observed in industrialized countries. It may be associated with physical violence or occur in isolation. The essential clinical sign is height and weight retardation, but malnutrition also causes a variety of internal and bone lesions, which lead to neuropsychological sequelae and death. We report a rare case of death by malnutrition in a female child aged 6½ months. The infant presented height and weight growth retardation and internal lesions related to prolonged protein,energy malnutrition (fat and muscle wasting, thymic atrophy, liver steatosis) resulting in a picture of marasmus or kwashiorkor. We detail the positive and negative criteria that established the diagnosis of abuse, whereas the parents had claimed a simple dietary error. [source] A review of nutrition in Duchenne muscular dystrophyJOURNAL OF HUMAN NUTRITION & DIETETICS, Issue 5 2009Z. E. Davidson Abstract Duchenne muscular dystrophy (DMD) is a recessive X linked genetic disorder characterised by progressive muscle weakness and reduced muscle tone. Affecting only boys, it limits life expectancy to approximately 20 years. A literature review was conducted using MEDLINE and the Cochrane Library, employing the term ,Duchenne muscular dystrophy'. A total of 1491 articles in English were recovered. These papers were searched thematically under the headings: body composition (n = 10), energy expenditure (n = 10), nutrition (n = 6), corticosteroid therapy (n = 55) and gene therapy (n = 199). Key dietetic practice points were identified relevant to nutritional management. Papers supporting these key themes were assigned a level of evidence and grade of recommendation. There is limited high-quality evidence to guide the nutritional management of boys with DMD. Currently, the majority of evidence is based on expert opinion and clinical expertise. Delayed growth, short stature, muscle wasting and increased fat mass are characteristics of DMD and impact on nutritional status and energy requirements. The early introduction of steroids has altered the natural history of the disease, but can exacerbate weight gain in a population already susceptible to obesity. Prior to commencing steroids, anticipatory guidance for weight management should be provided. Malnutrition is a feature of end stage disease requiring a multidisciplinary approach, such as texture modification and supplemental feeding. Micronutrient requirements are yet to be determined but, as a result of corticosteroid treatment, vitamin D and calcium should be supplemented. Some evidence exists supporting supplementation with creatine monohydrate to improve muscle strength. More research is needed to provide a higher quality of evidence for dietitians working within this area. [source] A service evaluation to determine the effectiveness of current dietary advice in treating human immunodeficiency virus-associated weight loss and to highlight potential service improvementsJOURNAL OF HUMAN NUTRITION & DIETETICS, Issue 4 2008C.A. Hunt Background:, Weight loss and muscle wasting are experienced by many patients with human immunodeficiency virus (HIV) (Grinspoon et al., 2003). Malnutrition is an important predicator of morbidity and mortality; people who are malnourished who received antiretroviral treatment are six times more likely to die than those who are adequately nourished (Paton et al., 2006). The physical manifestations of muscle wasting can have significant psychosocial implications for HIV patients (Power et al., 2003; Sattler, 2003). The aim of this study to evaluate provision of dietetic care to patients referred for acute weight loss advice and identify areas for potential service improvement. Methods:, The data were gathered from the departmental dietetic activity statistics in 2007, diagnosis code ,HIV , acute weight loss'. Fifty-nine cards were located and baseline weight, height and body mass index (BMI) were recorded (two female, 57 male). Qualitative data on dietetic intervention were extracted from record cards , little and often eating approach, food fortification (FF), high energy high protein oral nutritional supplement (ONS) prescribed. Data were collected on body image, exercise and weight at follow-up visits during 2007. Results:, Forty-three percent of the patients referred for ,HIV-acute weight loss' were lost to follow-up. Forty-seven percent of the remaining patients had a BMI <20 kg m,2. Following their initial dietetic intervention, 81% of these patients had gained weight at the first follow-up. All had received nutritional counselling on little and often eating approach and FF; 75% had ONS prescribed. Average weight gain with nutritional counselling alone was 1.3 kg (2.1 kg) and for nutritional counselling plus supplementation was 2.1 kg (1.8 kg). This represented 2.5% (4.1%) and 3.9% (3.4%) weight gain, respectively. Discussion:, This evaluation has highlighted that patient follow-up frequency is an area for service improvement. Fifty-three per cent of patients (excluding those lost to follow up) had a BMI ,20 kg m,2 and were inaccurately recorded in the statistics as being referred for ,HIV-acute weight loss'. Fifty-two percent of these patients reported lipodystrophy and body image concerns, similar to findings of other studies. Fifty-six percent reported weight improvements following dietetic consultation. Body image is a frequent referral trigger, therefore improvements should be made to identify and treat patients with body shape issues. Conclusions:, Dietitians are effective at achieving weight gain in HIV positive patients with a BMI <20 kg m,2 using nutritional counselling methods with or without oral nutritional supplementation; these patients experienced a 3.3% weight gain. Strategies need to be implemented to reduce the number of patients lost to follow-up, as weight loss is a key morbidity and mortality indicator in HIV. References, Grinspoon, S. & Mulligan, K. (2003) Weight loss and wasting in patients infected with HIV. Clin. Infect. Dis.36 (Suppl. 2): 69,78. Nerad, J., Romeyn, M., Silverman, E., Allen-Reid, J., Dieterich, D., Merchant, J., Pelletier, V., Tinnerello, D. & Fenton, M. (2003) General nutritional management in patients infected with HIV. Clin. Infect. Dis.36 (Suppl. 2): 52,62. Ockenga, J., Grimble, R., Jonkers-Schuitema, C., Macallan, D., Melchior, J.C., Sauerwein, H.P., Schwenk, A. & Suttmann, U. (2006) ESPEN guidelines on enteral nutrition: wasting in HIV and other chronic infectious diseases. Clin. Nutr.25, 319,329. Paton, N.I., Sangeetha, S., Earnest, A. & Bellamy, R. (2006) The impact of malnutrition on survival and the CD4 count response in HIV-infected patients starting antiretroviral therapy. HIV Med.7, 232,330. Power, R., Tate, H.L., McGill, S.M. & Taylor, C. (2003) A qualitative study of the psychosocial implications of lipodystrophy syndrome on HIV positive individuals. Sex. Transm. Infect.79, 137,141. Sattler, F. (2003) Body habitus changes related to lipodystrophy. Clin. Infect. Dis36 (Suppl. 2): 84,90. [source] Myotonic dystrophy 1 in the nervous system: From the clinic to molecular mechanismsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2008Mario Bermúdez de León Abstract Myotonic dystrophy type 1 (DM1) is a dominant neuromuscular disorder caused by the expansion of trinucleotide CTG repeats in the 3,-untranslated region (3,-UTR) of the DMPK gene. Prominent features of classical DM1 are muscle wasting and myotonia, whereas mental retardation is distinctive for congenital DM1. The main nervous system symptoms of DM1 are cognitive impairment, neuroendocrine dysfunction, and personality and behavior abnormalities. It is thought that expansion of CTG repeats causes DM1 pathology through different molecular mechanisms; however, a growing body of evidence indicates that an RNA gain-of-function mechanism plays a major role in the disease development. At the skeletal muscle level, three main molecular events can be distinguished in this model: 1) formation of nuclear foci that are composed at least of mutant DMPK mRNA and recruited RNA-binding proteins, such as splicing regulators and transcription factors; 2) disturbance of alternative splicing of specific genes; and 3) impairment of cell differentiation. Contrasting with the substantial advances in understanding DM1 muscle pathology, the molecular basis of DM1 in the nervous system has just started to be revealed. This review focuses in the DM1 nervous system pathology and provides an overview of the genetic and molecular studies analyzing the effects of the DMPK gene CUG expanded repeats on cell function in neuronal systems. A comparison between the molecular mechanisms of DM1 in the skeletal muscle and those identified in DM1 nervous system models is provided. Finally, future directions in the study of DM1 in the nervous system are discussed. © 2007 Wiley-Liss, Inc. [source] Inherited myopathy of great DanesJOURNAL OF SMALL ANIMAL PRACTICE, Issue 5 2006A. Lujan Feliu-Pascual A hereditary, non-inflammatory myopathy occurring in young great Danes with distinctive histological features in muscle biopsy specimens is reviewed. Onset of clinical signs is usually before one year of age and both sexes are affected. Clinical signs are characterised by exercise intolerance, muscle wasting, and an exercise-induced tremor. Although most affected dogs have a severe form of the disease, occasional dogs may have a less pronounced form and survive into adulthood with an acceptable quality of life. Litters containing affected puppies are born to clinically unaffected parents, and an autosomal recessive pattern of inheritance is likely. All recorded cases have had fawn or brindle coat coloration. Elevated serum creatinine kinase concentrations and spontaneous electrical activity in skeletal muscles are frequently found. While originally reported (Targett and others 1994) as a central core myopathy in this breed, the histochemical characteristics of the distinct cytoarchitectural structures differ from those of the well-characterised central core myopathy in human beings. In fact, these structures differ from any known myopathy in human beings and likely represents a unique non-inflammatory myopathy affecting dogs. Until this myopathy is characterised further, the name inherited myopathy in great Danes is suggested. [source] AUTOMIC FAILURE AND NORMAL PRESSURE HYDROCEPHALUS IN A PATIENT WITH CHRONIC DEMYELINATING INFLAMMATORY NEUROPATHYJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2002M. Laurà A 75-year-old man with HCV hepatitis developed at the age of 70 presented with rest and action tremor localized at both hands and progressive cognitive impairment with memory loss. Four years later he begun to complain of progressive fatigue, occasional falls, numbness at the extremities and orthostatic hypotension. One month after admission, he rapidly worsened with inability to walk, mainly because of autonomic failure. Neurological examination revealed gait disturbances, including a wide base of support and short stride, slurred speech, reduction of upward gaze, rest and action tremor at both hands, intrinsic hand muscle and anterior tibialis muscle wasting and weakness on both sides, absent deep tendon reflexes, loss of vibration sense at lower limbs, and bilateral pes cavus. Routine laboratory studies, autoantibodies, thyroid function, neoplastic markers and immunoelectrophoresis were normal. Cryoglobulins were absent, whereas CSF protein content was increased (142 mg/dl). Autonomic nervous system investigation detected severe orthostatic hypotension. Nerve conduction studies showed absent sensory potentials and a marked reduction of compound motor action potential amplitudes and of motor conduction velocities. A sural nerve biopsy revealed remarkable onion bulb-like changes, endoneurial and perivascular infiltrations of inflammatory cells. Psychometric tests showed mild cognitive impairment. Brain MRI was consistent with normotensive hydrocephalus. The findings indicated the presence of chronic inflammatory demyelinating polyneuropathy, autonomic nervous system involvement and normal pressure hydrocephalus. A condition of multiple system atrophy (MSA) might be taken into account, even if somatic peripheral nerve involvement may rarely occur in MSA. Moreover the normal pressure hydrocephalus could be due to the high protein content in CSF (Fukatsu R et al., 1997). [source] Reduced Nerve Blood Flow In Diabetic Rats Is A Reflection Of Hindlimb Muscle WastingJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 3 2000Dr Tomlinson We examined the influence of muscle wasting, as a result of streptozotocin-induced diabetes, on sciatic nerve laser Doppler flux (SNLDF), as an index of nerve blood flow, and conduction velocity (NCV). We compared dietary-restricted weight-reduced non-diabetic rats with controls and with diabetic rats and we studied the effects of clenbuterol, an anabolic ,-adrenoceptor agonist, in control and diabetic rats. Dietary restriction reduced the weights of hindlimb muscles,extensor digitorum longus, soleus and gastrocnemius,half as much as did streptozotocin-diabetes and clenbuterol increased muscle weights in control and diabetic rats. This gave a hierarchy of muscle weights in the order,clenbuterol-controls, untreated controls, weight-reduced non-diabetics, clenbuterol-diabetics and untreated diabetics. Diabetes without treatment reduced SNLDF by 51% (p < 0.01); dietary restriction by 25% (p < 0.01) and there were proportional increases associated with clenbuterol treatment. Combined muscle weights regressed closely with SNLDF (r2=0.69; p < 0.001) and, when the latter was expressed relative to muscle weights, a similar value was obtained for all five groups,there were no significant differences. Thus, sciatic nerve blood flow is closely related to hindlimb muscle weight and the effect of diabetes on nerve blood flow may be secondary to muscle wasting. Sciatic/tibialis motor and sensory conduction velocities were also reduced by muscle wasting in the dietary restricted group of non-diabetic rats, but, unlike nerve Doppler flux, it was unaffected by clenbuterol. [source] Muscular Dystrophy in female DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2001G. Diane Shelton The most common form of muscular dystrophy in dogs and humans is caused by mutations in the dystrophin gene. The dystrophin gene is located on the X chromosome, and, therefore, disease-causing mutations in dystrophin occur most often in males. Therefore, females with dystrophin deficiency or other forms of muscular dystrophy may be undiagnosed or misdiagnosed. Immunohisto-chemistry was used to analyze dystrophin and a number of other muscle proteins associated with muscular dystrophy in humans, including sarcoglycans and laminin ,2, in muscle biopsy specimens from 5 female dogs with pathologic changes consistent with muscular dystrophy. The female dogs were presented with a variety of clinical signs including generalized weakness, muscle wasting, tremors, exercise intolerance, gait abnormalities, and limb deformity. Serum creatine kinase activity was variably high. One dog had no detectable dystrophin in the muscle; another was mosaic, with some fibers normal and others partly dystrophin-deficient. A 3rd dog had normal dystrophin but no detectable laminin ,2. Two dogs could not be classified. This study demonstrates the occurrence of dystrophin- and laminin ,2-associated muscular dystrophy and the difficulty in clinical diagnosis of these disorders in female dogs. [source] Altered mRNA splicing of dystrophin in type 1 myotonic dystrophyMUSCLE AND NERVE, Issue 2 2007Masayuki Nakamori MD Abstract Myotonic dystrophy type1 (DM1) is a multisystemic disorder caused by a CTG repeat expansion in the DMPK gene. Aberrant mRNA splicing of several genes has been reported to contribute to some of the symptoms, including myotonia and insulin resistance, but the cause of muscle wasting is unknown. Dystrophin is a cytoskeletal protein that is required for structural stability and signaling at the sarcolemma and has several spliced isoforms. We investigated the alternative splicing of dystrophin in skeletal and cardiac muscle of DM1 patients by using reverse transcriptase,polymerase chain reaction and found that dystrophin isoforms lacking exon 71 or 78, which is suggested to encode an important region for protein binding and hydrophobicity, were significantly increased. We suggest that the aberrantly spliced dystrophin is responsible for the muscle wasting in DM1. Muscle Nerve, 2007 [source] Oxidative stress, chronic disease, and muscle wastingMUSCLE AND NERVE, Issue 4 2007Jennifer S. Moylan PhD Abstract Underlying the pathogenesis of chronic disease is the state of oxidative stress. Oxidative stress is an imbalance in oxidant and antioxidant levels. If an overproduction of oxidants overwhelms the antioxidant defenses, oxidative damage of cells, tissues, and organs ensues. In some cases, oxidative stress is assigned a causal role in disease pathogenesis, whereas in others the link is less certain. Along with underlying oxidative stress, chronic disease is often accompanied by muscle wasting. It has been hypothesized that catabolic programs leading to muscle wasting are mediated by oxidative stress. In cases where disease is localized to the muscle, this concept is easy to appreciate. Transmission of oxidative stress from diseased remote organs to skeletal muscle is thought to be mediated by humoral factors such as inflammatory cytokines. This review examines the relationship between oxidative stress, chronic disease, and muscle wasting, and the mechanisms by which oxidative stress acts as a catabolic signal. Muscle Nerve, 2007 [source] Proteomic profiling of antisense-induced exon skipping reveals reversal of pathobiochemical abnormalities in dystrophic mdx diaphragmPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 3 2009Philip Doran Abstract The disintegration of the dystrophin,glycoprotein complex represents the initial pathobiochemical insult in Duchenne muscular dystrophy. However, secondary changes in signalling, energy metabolism and ion homeostasis are probably the main factors that eventually cause progressive muscle wasting. Thus, for the proper evaluation of novel therapeutic approaches, it is essential to analyse the reversal of both primary and secondary abnormalities in treated muscles. Antisense oligomer-mediated exon skipping promises functional restoration of the primary deficiency in dystrophin. In this study, an established phosphorodiamidate morpholino oligomer coupled to a cell-penetrating peptide was employed for the specific removal of exon 23 in the mutated mouse dystrophin gene transcript. Using DIGE analysis, we could show the reversal of secondary pathobiochemical abnormalities in the dystrophic diaphragm following exon-23 skipping. In analogy to the restoration of dystrophin, ,-dystroglycan and neuronal nitric oxide synthase, the muscular dystrophy-associated differential expression of calsequestrin, adenylate kinase, aldolase, mitochondrial creatine kinase and cvHsp was reversed in treated muscle fibres. Hence, the re-establishment of Dp427 coded by the transcript missing exon 23 has counter-acted dystrophic alterations in Ca2+ -handling, nucleotide metabolism, bioenergetic pathways and cellular stress response. This clearly establishes the exon-skipping approach as a realistic treatment strategy for diminishing diverse downstream alterations in dystrophinopathy. [source] Inhibitors of COX activity preserve muscle mass in mice bearing the Lewis lung carcinoma, but not the B16 melanomaRESEARCH IN NURSING & HEALTH, Issue 2 2006Erin Graves Abstract Tumor-induced skeletal muscle wasting (SMW) contributes to the fatigue and weakness experienced by persons with cancer cachexia. Tumor necrosis factor-alpha (TNFa) and cyclooxygenase (COX) activity have been implicated in SMW in some animal models of cancer cachexia. We report that indomethacin, a nonspecific inhibitor of COX, and NS398, a specific inhibitor of COX2, preserved muscle mass and reduced type 1 TNF receptors in muscles of mice bearing the Lewis lung carcinoma, but not in mice bearing the B16 melanoma. These data suggest that tumor-induced SMW can occur via a COX2-independent pathway. The COX2-dependent pathway may involve reducing the catabolic effects of TNFa in muscle. Further study is needed to understand the relationship between COX and SMW, and whether patients with cancer cachexia might benefit from COX inhibitors. © 2006 Wiley Periodicals, Inc. Res Nurs Health 29:87,97, 2006 [source] Can an NSAID a day keep muscle wasting away?THE JOURNAL OF PHYSIOLOGY, Issue 24 2009Carolyn A. Greig No abstract is available for this article. [source] Comparison of mechanomyography and acceleromyography for the assessment of rocuronium induced neuromuscular block in myotonic dystrophy type 1ANAESTHESIA, Issue 6 2010L. E. H. Vanlinthout Summary We measured acceleromyography and mechanomyography simultaneously with monitoring of rocuronium-induced neuromuscular block in four patients with myotonic dystrophy type 1. Furthermore, we compared neuromuscular block measures from these patients with those from normal controls from previous studies. In myotonic dystrophy type 1 patients, the dose-response curve obtained with acceleromyography was steeper and right-shifted compared with that obtained using mechanomyography. However, the effective doses to produce 95% neuromuscular block determined with both acceleromyography and mechanomyography were similar to each other and to values found in normal patients. In the three myotonic dystrophy type 1 patients with mild to moderate disease, times to recovery from block were similar to those observed in normal controls. In both patients and normal controls, neuromuscular block recovered faster with acceleromyography. However, in one patient with severe muscle wasting, recovery of neuromuscular block was prolonged. We conclude that mechanomyography and acceleromyography cannot be used interchangeably to monitor neuromuscular block in myotonic dystrophy type 1 patients. [source] Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weaknessANNALS OF NEUROLOGY, Issue 5 2006Terumi Murakami MD Objective The fukutin gene (FKTN) is the causative gene for Fukuyama-type congenital muscular dystrophy, characterized by rather homogeneous clinical features of severe muscle wasting and hypotonia from early infancy with mental retardation. In contrast with the severe dystrophic involvement of skeletal muscle, cardiac insufficiency is quite rare. Fukuyama-type congenital muscular dystrophy is one of the disorders associated with glycosylation defects of ,-dystroglycan, an indispensable molecule for intra-extra cell membrane linkage. Methods Protein and functional analyses of ,-dystroglycan and mutation screening of FKTN and other associated genes were performed. Results Surprisingly, we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation. One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old. Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of ,-dystroglycan and reduced laminin binding ability. One cardiac muscle that underwent biopsy showed altered glycosylation of ,-dystroglycan similar to that observed in a Fukuyama-type congenital muscular dystrophy patient. Interpretation FKTN mutations could cause much wider spectrum of clinical features than previously perceived, including familial dilated cardiomyopathy and mildest limb girdle muscular dystrophy. Ann Neurol 2006 [source] Constitutive activation of MAPK cascade in acute quadriplegic myopathyANNALS OF NEUROLOGY, Issue 2 2004Simone Di Giovanni MD Acute quadriplegic myopathy (AQM; also called "critical illness myopathy") shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber-specific ubiquitin/proteosome pathways (eg, atrogin-1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF),,/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF-, receptors, p38 MAPK, c-jun, and c-myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF-, pathway in myofibers. The acute stimulation of the TGF-,/MAPK pathway, coupled with the inactivity-induced atrogin-1/proteosome pathway, leads to the acute muscle loss seen in AQM patients. Ann Neurol 2004 [source] Can the outcome of open carpal tunnel release be predicted?: a review of the literatureANZ JOURNAL OF SURGERY, Issue 1-2 2010Alexandra Turner Abstract Carpal tunnel syndrome is a common condition affecting 1% of the population. Open carpal tunnel release is the most commonly performed procedure for this condition. About 70,90% of patients have good to excellent long-term outcomes with open carpal tunnel release. The remainder have poor outcomes. An understanding of factors which predict a poor outcome following open carpal tunnel release would be of benefit during preoperative counselling, and provides more accurate expectations of outcomes after surgery. We reviewed the published literature in the English language over the last 20 years in an attempt to ascertain predictors of poor outcomes following open carpal tunnel release. Patient factors such as age, sex and weight were not found to be predictors of a poor outcome following open carpal tunnel release. Similarly, physical examination had little usefulness, save for abductor pollicis wasting, for predicting post-surgical functional limitations, symptoms or satisfaction. Co-morbid conditions such as diabetes, poor health status, thoracic outlet syndrome, double crush, alcohol and smoking have a worse prognosis. Normal nerve conduction studies preoperatively, direct nerve surgery such as neurolysis, abductor pollicis brevis muscle wasting and workers' compensation cases which involve lawyers preoperatively are all associated with worse outcomes. Postoperative physiotherapy may accelerate recovery but neither modifies functional recovery or reduces symptom occurrence. [source] Inhibition of defective adenylosuccinate lyase by HNE: A neurological disease that may be affected by oxidative stressBIOFACTORS, Issue 1-4 2005C. Crifò Abstract Adenylosuccinate lyase is an enzyme of fumarase superfamily that participates in the purine biosynthetic pathway, catalysing the nonhydrolytic cleavage of succinyl groups from SAICA ribotide and adenylosuccinate. Enzyme defects are associated with a human inherited disease, which arises from single point mutations to the gene and results in mild to severe psychomotor retardation, epilepsy, muscle wasting, and autistic features. Adenylosuccinate lyase activity is lost to a different extent in the patients. Diminished levels of enzyme have been attributed to loss of catalytic activity, protein instability, or environmental factors. P100A/D422Y mutation represents a feasible model for studying the effect of cell milieu on the activity of the impaired enzyme. The defective enzyme is inhibited by micromolar concentrations of trans-4-hydroxy-2-nonenal (HNE), a major product of membrane peroxidation that has been found to accumulate in brain tissues of patients with neurodegenerative disorders. It is suggested that inactivation of defective adenylosuccinate lyase by HNE and other membrane peroxidation products may account, at least in part, for the impairment of neurological functions and recurrent worsening of the symptoms. [source] | ||||||||||||||||||||||||||||