Search

Purpose: We documented speech and voice characteristics associated with oculopharyngeal muscular dystrophy (OPMD). Although it is a rare disease, OPMD offers the opportunity to study the impact of myopathic weakness on speech production in the absence of neurologic deficits in a relatively homogeneous group of speakers. Methods: Twelve individuals with OPMD and 12 healthy age-matched controls underwent comprehensive assessment of the speech mechanism including spirometry (respiratory support), nasometry (resonance balance), phonatory measures (pitch, loudness, and quality), articulatory measures (diadochokinetic rates, segment duration measures, spectral moments, and vowel space), tongue-to-palate strength measures during maximal isometric and speechlike tasks, quality-of-life questionnaire, and perceptual speech ratings by listeners. Results: Individuals with OPMD had substantially reduced tongue strength compared to the controls. However, little impact on speech and voice measures or on speech intelligibility was observed except for slower diadochokinetic rates. Conclusions: Despite having less than half the maximal tongue strength of healthy controls, the individuals with OPMD exhibited minimal speech deficits. The threshold of weakness required for noticeable speech impairment may not have been reached by this group of adults with OPMD., Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic myopathic disease characterized by ptosis and dysphagia. OPMD symptoms generally appear in middle age with ptosis and dysphagia progressing slowly over many [...]

BACKGROUND/OBJECTIVES: Nutritional issues that are associated with Duchenne muscular dystrophy (DMD) remain poorly understood. The aim of this analysis was to describe and explore longitudinal observations of body mass index (BMI) in a cohort of children with DMD. SUBJECTS/METHODS: Anthropometric and clinical characteristics were collected retrospectively and longitudinally for boys with DMD seen in two large neuromuscular clinics. BMI Z-scores were determined using the Centers for Disease Control and Prevention reference values for children (2000). RESULTS: Medical records (n = 193) were examined from which 75% were included for analysis. The mean age of the cohort at the time of data collection was 11.9 years, with 72% of patients currently or previously using steroids. The highest prevalence of obesity based on the BMI Z-score was 50% at the age of 10 years. Longitudinally, BMI Z-scores from the age of 2 to 12 years plot approximately one s.d. above the mean, after which there is a marked and progressive decline. BMI gainers were identified for whom BMI Z-score increased by 1.65 units compared with the 0.09 units in non-gainers. BMI gainers were younger when they had their first BMI measurement (5.9 vs 7.2 years), and this measure was significantly lower compared with the non-gainers (BMI Z-score: 0.04 vs 1.17). In this cohort, BMI was associated with age, ambulatory status and lung function. CONCLUSIONS: This study demonstrates that boys with DMD using steroid therapy experience shifts in BMI. A declining BMI appears to be associated with increasing age. Interpretation of growth patterns is limited here by a lack of normative growth references in DMD. European Journal of Clinical Nutrition (2014) 68, 892-897; doi: 10.1038/ejcn.2014.93; published online 14 May 2014, INTRODUCTION Duchenne muscular dystrophy (DMD) is the most common and severe muscular dystrophy of childhood. Affecting 1 in 3500 boys, the disease causes progressive and relentless muscle weakness, limiting life [...]

The ubiquitously expressed multifunctional cytolinker protein plectin is essential for muscle fiber integrity and myofiber cytoarchitecture. Patients suffering from plectinopathy-associated epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and mice lacking plectin in skeletal muscle display pathological desmin-positive protein aggregation and misalignment of Z-disks, which are hallmarks of myofibrillar myopathies (MFMs). Here, we developed immortalized murine myoblast cell lines to examine the pathogenesis of plectinopathies at the molecular and single cell level. Plectin-deficient myotubes, derived from myoblasts, were fully functional and mirrored the pathological features of EBS-MD myofibers, including the presence of desmin-positive protein aggregates and a concurrent disarrangement of the myofibrillar apparatus. Using this cell model, we demonstrated that plectin deficiency leads to increased intermediate filament network and sarcomere dynamics, marked upregulation of HSPs, and reduced myotube resilience following mechanical stretch. Currently, no specific therapy or treatment is available to improve plectin-related or other forms of MFMs; therefore, we assessed the therapeutic potential of chemical chaperones to relieve plectinopathies. Treatment with 4-phenylbutyrate resulted in remarkable amelioration of the pathological phenotypes in plectin-deficient myotubes as well as in plectin-deficient mice. Together, these data demonstrate the biological relevance of the MFM cell model and suggest that this model has potential use for the development of therapeutic approaches for EBS-MD., Introduction Protein aggregation is the characteristic pathomorphological hallmark of major neurodegenerative disorders such as Alzheimer's and Parkinson's disease, various forms of dementia, and amyotrophic lateral sclerosis. In analogy to this [...]

Patients with Duchenne muscular dystrophy (DMD) have reduced muscle function due to chronic muscle damage, inflammation, oxidative stress, and reduced oxidative capacity. Resveratrol reduces inflammation and oxidative stress, and increases oxidative capacity in other disease models. The purpose of this study was to determine the effects of resveratrol on muscle function, muscle pathology, and oxidative capacity in young mdx mice. For this, 4- to 5-week-old male mdx mice were randomized into control or resveratrol-treated groups and given resveratrol (100 mg/kg body mass) or an equal volume of water by gavage every other day for 8 weeks. Muscle function was assessed pre- and post-treatment. Central nucleation, total immune cell infiltrate, oxidative stress, and oxidative capacity were measured post-treatment. Resveratrol mediated substantial improvements in rotarod performance and in-situ peak tension by 53% and 17%, respectively, and slight improvements in central nucleation and oxidative stress. Resveratrol did not affect total immune cell infiltrate at 12 weeks of age, and had no effect on oxidative capacity. Resveratrol improves muscle function in mdx mice despite small changes in muscle pathology. The likely mechanism is a resveratrol-mediated reduction in immune cell infiltrate at the early stages of this disease, as previously reported by our laboratory. Key words: Duchenne muscular dystrophy, resveratrol, inflammation, oxidative stress, oxidative capacity, muscle damage, utrophin. Les patients atteints de la dystrophie musculaire de Duchesne (DMD) presentent une fonction musculaire reduite a cause d'un dommage musculaire chronique, d'une inflammation, d'un stress oxydant et d'une capacite oxydante reduite. Le resveratrol reduit l'inflammation et le stress oxydant, et il accroit la capacite oxydante dans d'autres modeles de maladies. Le but de cette etude etait d'evaluer les effets d'un traitement au resveratrol sur la fonction musculaire, la pathologie du muscle et la capacite oxydante de jeunes souris mdx. Des souris males mdx de 4-5 semaines ont ete reparties aleatoirement en groupes controles ou traites au resveratrol, et elles ont re^u le resveratrol (100 mg/kg) ou de l'eau a tous les deux jours pendant 8 semaines. La fonction musculaire a ete evaluee avant et apres le traitement. La nucleation centrale, l'infiltrat immunitaire total, le stress oxydant et la capacite oxydante ont ete mesures apres le traitement. Le resveratrol permettait d'obtenir des ameliorations substantielles de la performance au Rotarod et du pic de la tension in situ de 53% et 17%, respectivement, et une legere amelioration sur le plan de la nucleation centrale et du stress oxydant. Le resveratrol n'affectait pas l'infiltrat immunitaire total a l'age de 12 semaines et n'avait pas d'effet sur la capacite oxydante. Le resveratrol ameliore la fonction musculaire des souris mdx malgre de faibles changements sur le plan de la pathologie du muscle. Le mecanisme probable consiste en une reduction de l'infiltrat immunitaire dependante du resveratrol a des etapes precoces de cette maladie, comme rapporte precedemment par notre laboratoire. [Traduit par la Redaction] Mots-cles: dystrophie musculaire de Duchesne, resveratrol, inflammation, stress oxydant, capacite oxydante, dommage musculaire, utrophine., Introduction Duchenne muscular dystrophy (DMD) is the most common lethal genetic disease, affecting 1 in 3500 live male births (Hoffman et al. 1987). This disease is caused by mutations in [...]

Purpose: This prospective investigation evaluates oral weakness and its impact on swallow function, weight, and quality of life in patients with oculopharyngeal muscular dystrophy (OPMD). Method: Intraoral pressure, swallow pressure, and endurance were measured using an Iowa Oral Performance Instrument in participants with OPMD and matched controls. Timed water swallow, weight, and quality of life were also assessed. Results: Participants with OPMD were weaker than controls. Oral weakness impacted strength, swallow pressure, swallow capacity, swallow volume, swallow time, and quality of life. Tongue endurance was not affected by oral weakness. Conclusion: This investigation provides further insight into the swallow function of patients with myopathic disease. Muscle fiber loss leads to weakness, which results in reductions in swallow function and quality of life. Weight and endurance are not greatly altered. KEY WORDS: OPMD, swallow pressure, pressure reserve, SWAL-QOL, timed water swallow, IOPI, There is a paucity of research on the swallow deficits in patients with oculopharyngeal muscular dystrophy (OPMD), a rare myopathic disease with a high incidence in Hispanic New Mexicans (Becher [...]

The double knockout mouse for utrophin and dystrophin ([utr.sup.-/-]/mdx) has been proposed to be a better model of Duchenne Muscular Dystrophy (DMD) than the mdx mouse because the former displays more similar muscle pathology to that of the DMD patients. In this paper the properties of action potentials (APs) and [Ca.sup.2+] transients elicited by single and repetitive stimulation were studied to understand the excitation-contraction (EC) coupling alterations observed in muscle fibers from mdx and [utr.sup.-/-]/mdx mice. Based on the comparison of the AP durations with those of fibers from wild-type (WT) mice, fibers from both mdx and [utr.sup.-/-]/mdx mice could be divided in two groups: fibers with WT-like APs (group 1) and fibers with significantly longer APs (group 2). Although the proportion of fibers in group 2 was larger in [utr.sup.-/-]/mdx (36%) than in mdx mice (27%), the [Ca.sup.2+] release elicited by single stimulation was found to be similarly depressed (32-38%) in [utr.sup.-/-]/mdx and mdx fibers compared with WT counterparts regardless of the fiber's group. Stimulation at 100 Hz revealed that, with the exception of those from [utr.sup.-/-]/mdx mice, group 1 fibers were able to sustain [Ca.sup.2+] release for longer than group 2 fibers, which displayed an abrupt limitation even at the onset of the train. The differences in behavior between fibers in groups 1 and 2 became almost unnoticeable at 50 Hz stimulation. In general, fibers from [utr.sup.-/-]/mdx mice seem to display more persistent alterations in the EC coupling than those observed in the mdx model. muscular dystrophy; mammalian skeletal muscle; fluorescence microscopy doi: 10.1152/ajpcell.00428.2009.

Calcineurin activation ameliorates the dystrophic pathology of hindlimb muscles in mdx mice and decreases their susceptibility to contraction damage. In mdx mice, the diaphragm is more severely affected than hindlimb muscles and more representative of Duchenne muscular dystrophy. The constitutively active calcineurin A[alpha] transgene (CnA[alpha]) was overexpressed in skeletal muscles of mdx (mdx can[[alpha].sup.*]) mice to test whether muscle morphology and function would be improved. Contractile function of diaphragm strips and extensor digitorum longus and soleus muscles from adult mdx CnA[[alpha].sup.*] and mdx mice was examined in vitro. Hindlimb muscles from mdx CnA[[alpha].sup.*] mice had a prolonged twitch time course and were more resistant to fatigue. Because of a slower phenotype and a decrease in fiber cross-sectional area, normalized force was lower in fast- and slow-twitch muscles of mdx CnA[[alpha].sup.*] than mdx mice. In the diaphragm, despite a slower phenotype and a ~35% reduction in fiber size, normalized force was preserved. This was likely mediated by the reduction in the area of the diaphragm undergoing degeneration (i.e., mononuclear cell and connective and adipose tissue infiltration). The proportion of centrally nucleated fibers was reduced in mdx CnA[[alpha].sup.*] compared with mdx mice, indicative of improved myofiber viability. In hindlimb muscles of mdx mice, calcineurin activation increased expression of markers of regeneration, particularly developmental myosin heavy chain isoform and myocyte enhancer factor 2A. Thus activation of the calcineurin signal transduction pathway has potential to ameliorate the mdx pathophysiology, especially in the diaphragm, through its effects on muscle degeneration and regeneration and endurance capacity. muscle regeneration; muscular dystrophy; skeletal muscle; muscle contraction

Duchenne muscular dystrophy is caused by the absence of the protein dystrophin. Dystrophin's function is not known, but its cellular location and associations with both the force-generating contractile core and membrane-spanning entities suggest a role in mechanically coupling force from its intracelhilar origins to the fiber membrane and beyond. We report here the presence of destructive contractile activity in himbrical muscles from dystrophin-deficient (mdx) mice during nominally quiescent periods following exposure to mechanical stress. The ectopic activity, which was observable microscopically, resulted in longitudinal separation and clotting of fiber myoplasm and was absent when calcium ([Ca.sup.2+]) was removed from the bathing medium. Separation and clotting of myoplasm were also produced in dystrophin-deficient muscles by local application of a [Ca.sup.2+] ionophore to create membrane breaches in the absence of mechanical stress, whereas muscles from control mice tolerated ionophore-induced entry of [Ca.sup.2+] without damage. These observations suggest a failure cascade in dystrophindeficient fibers that 1) is initiated by a stress-induced influx of extracelhilar [Ca.sup.2+], causing localized activation to continue after cessation of stimulation, and 2) proceeds as the persistent local activation, combined with reduced lateral mechanical coupling between the contractile core and the extracellular matrix, results in longitudinal separation of myoplasm in nonactivated regions of the fiber. This mechanism invokes both the membrane stabilization and the mechanical coupling functions frequently proposed for dystrophin and suggests that, whereas the absence of either function alone is not sufficient to cause fiber failure, their combined absence is catastrophic. skeletal muscle; muscle damage; dystrophin

Duchenne muscular dystrophy (DMD) is a lethal X-linked disease caused by the absence of functional dystrophin. Abnormal excitation-contraction (E-C) coupling has been reported in dystrophic muscle fibers from mdx mice, and alterations in E-C coupling components may occur as a direct result of dystrophin deficiency. We hypothesized that muscle-specific overexpression of insulin-growth factor-1 (IGF-I) would reduce E-C coupling failure in mdx muscle. Mechanically skinned extensor digitorum longus muscle fibers from mdx mice displayed a faster decline in depolarization-induced force responses (DIFR); however, there were no differences in sarcoplasmic reticulum (SR)-mediated [Ca.sup.2+] resequestration or in the properties of the contractile apparatus when compared with nondystrophic controls. The rate of DIFR decline was restored to control levels in fibers from transgenic mdx mice that overexpressed IGF-I in skeletal muscle (mdx/IGF-I mice). Dystrophic muscles have a lower transcript level of a specific dihydropyridine receptor (DHPR) isoform, and IGF-I-mediated changes in E-C coupling were associated with increased transcript levels of specific DHPR isoforms involved in [Ca.sup.2+] regulation. Importantly, IGF-I overexpression also increased the sensitivity of the contractile apparatus to [Ca.sup.2+]. The results demonstrate that IGF-I can ameliorate fundamental aspects of E-C coupling failure in dystrophic muscle fibers and that these effects are important for the improvements in cellular function induced by this growth factor. growth factor; muscular dystrophy; skinned fiber

Limb-girdle muscular dystrophy types 2E and F are characterized by skeletal muscle weakness and often cardiomyopathy and are due to mutations in the genes encoding [beta]- and [delta]-sarcoglycan. We previously demonstrated that loss of sarcoglycans in smooth muscle leads to constrictions of the microvasculature that contributes to the cardiac phenotype. It is unclear how vasculature abnormalities affect skeletal muscle. We injected recombinant [beta]- or [delta]-sarcoglycan adenoviruses into skeletal muscles of corresponding null mice. We hypothesized that the adenoviruses would not transduce vascular smooth muscle, and we would only target skeletal muscle. Indeed, sustained expression of intact sarcoglycan-sarcospan complex was noted at the sarcolemma, neuromuscular junction, myotendinous junction, and in peripheral nerve, but not in vascular smooth muscle. Gene transfer of the corresponding deleted sarcoglycan gene preserved sarcolemmal integrity, prevented pathological dystrophy and hypertrophy, and protected against exercised-induced damage. We conclude that vascular dysfunction is not a primary cause of [beta]- and [delta]-sarcoglycan-deficient muscular dystrophy. In addition, we show successful functional rescue of entire muscles after adenovirus-mediated gene delivery. Thus, virus-mediated gene transfer of sarcoglycans to skeletal muscle in combination with pharmacological prevention of cardiomyopathy constitute promising therapeutic strategies for limb-girdle muscular dystrophies.

The mdx mouse is a model for human Duchenne muscular dystrophy (DMD), an X-linked degenerative disease of skeletal muscle tissue characterized by the absence of the dystrophin protein. The mdx mice display a much milder phenotype than DMD patients. After the first week of life when all mdx muscles evolve like muscles of young DMD patients, mdx hindlimb muscles substantially compensate for the lack of dystrophin, whereas mdx diaphragm muscle becomes progressively affected by the disease. We used cDNA microarrays to compare the expression profile of 1,082 genes, previously selected by a subtractive method, in control and mdx hindlimb and diaphragm muscles at 12 time points over the first year of the mouse life. We determined that 1) the dystrophin gene defect induced marked expression remodeling of 112 genes encoding proteins implicated in diverse muscle cell functions and 2) two-thirds of the observed transcriptomal anomalies differed between adult mdx hindlimb and diaphragm muscles. Our results showed that neither mdx diaphram muscle nor mdx hindlimb muscles evolve entirely like the human DMD muscles. This finding should be taken under consideration for the interpretation of future experiments using mdx mice as a model for therapeutic assays. muscular dystrophy; mdx mice; complementary deoxyribonucleic acid microarray; differential gene expression

The dystrophin-glycoprotein complex (DGC) is a sarcolemmal complex whose defects cause muscular dystrophies. The normal function of this complex is not clear. We have proposed that this is a signal transduction complex, signaling normal interactions with matrix laminin, and that the response is normal growth and homeostasis. If so, the complex and its signaling should be altered in other physiological states such as atrophy. The amount of some of the DGC proteins, including dystrophin, [beta]-dystroglycan, and [alpha]-sarcoglycan, is reduced significantly in rat skeletal muscle atrophy induced by tenotomy. Furthermore, H-Ras, RhoA, and Cdc42 decrease in expression levels and activities in muscle atrophy. When the small GTPases were assayed after laminin or [beta]-dystroglycan depletion, H-Ras, Rac1, and Cdc42 activities were reduced, suggesting a physical linkage between the DGC and the GTPases. Dominant-negative Cdc42, introduced with a retroviral vector, resulted in fibers that appeared atrophic. These data support a putative role for the DGC in transduction of mechanical signals in muscle. syntrophin; sarcoglycan; dystroglycan; Cdc42; retrovirus; tenotomy

In dystrophic mice, a model of merosin-deficient congenital muscular dystrophy, laminin-2 mutations produce peripheral nerve dysmyelination and render Schwann cells unable to sort bundles of axons. The laminin receptor and the mechanism through which dysmyelination and impaired sorting occur are unknown. We describe mice in which Schwann cell--specific disruption of [beta]1 integrin, a component of laminin receptors, causes a severe neuropathy with impaired radial sorting of axons. [beta]1-null Schwann cells populate nerves, proliferate, and survive normally, but do not extend or maintain normal processes around axons. Interestingly, some Schwann cells surpass this problem to form normal myelin, possibly due to the presence of other laminin receptors such as dystroglycan and [alpha]6[beta]4 integrin. These data suggest that [beta]1 integrin links laminin in the basal lamina to the cytoskeleton in order for Schwann cells to ensheath axons, and alteration of this linkage contributes to the peripheral neuropathy of congenital muscular dystrophy.

Calpain 3 deficiency in limb girdle muscular dystrophy (LGMD) type 2A is associated with myonuclear apoptosis and profound perturbation of the I(kappa)B(alpha)/NF-(kappa)B pathway. Fluorescence microscopy has showed muscle biopsies of LGMD2A patients present apoptotic features associated with subsarcolemmal localization of NF-(kappa)B and selective nuclear accumulation of I(kappa)B(alpha).

The roles of MyoD, myogenin and Id.1 in regulating changes in muscle gene expression in response to spinal cord transection and during exercise in mice were investigated. The findings revealed that short-term passive exercises can reduce muscle atrophy occurring after spinal cord transection. Moreover, the increase in MyoD and myogenin expression which resulted in satellite cell activation was observed and characterized.

The contractile properties and the response of muscles from old mdx mice to low-impact, non-weight-bearing exercise were investigated. The mdx phenotype is very similar to the human Duchenne muscular dystrophy. Results reveal that muscles from old affected mice has decreased absolute twitch, diminished tetanic forces and longer contraction times compared to controls. However, muscles from mdx mice still responded to low-intensity exercise. The implications of these findings to muscular dystrophy patients are discussed.

The mdx mouse model for Duchene muscular dystrophy was utilized to determine the resting levels of intracellular Ca2+ based on the PE3 compartmentalization-resistant calcium-sensitive dye and fura 2-AM. Normal dystrophic myotubes have higher levels of resting intracellular Ca2+ and greater calcium leak channel activity compared to dystrophic fibroblasts. The abnormal levels of Ca2+ were caused by tearing at the dystrophic sarcolemma which initiates degradative processes.

Cardiomyopathy, as well as hereditary muscular dystrophy, may be related to a deficiency of the glycoprotein called adhalin, which is part of the structure that links muscle cells together. Cardiomyopathy is disease of the heart muscle and adhalin is associated with the protein dystrophin, some forms of which are deficient in muscular dystrophy. A 13-year-old boy with muscular dystrophy had muscle weakness, an enlarged heart, arrythmia, and congestive heart failure received a heart transplant. Biopsies of his thigh and heart muscles showed that the muscle cell membranes were broken down. The levels of adhalin and a related structural glycoprotein were extremely low in the thigh muscle and undetectable in the heart muscle. Various causes, including mutation of the adhalin gene, may cause adhalin deficiency.

Deficiency of protein dystrophin causes Duchenne muscular dystrophy, a X-chromosome-linked muscle-wasting disease, while the expression of mutant dystrophin leads to Becker muscular dystrophy. Examination of the dystrophin interaction with a large oligometric protein complex embedded in the sarcolemma and the identification of utrophin, a structurally related protein, help investigate possible genes causing various neuromuscular disorders.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the muscular dystrophy syndromes; unlike the X-linked syndromes such as Duchenne muscular dystrophy, the gene for facioscapulohumeral muscular dystrophy is dominant and is located on an autosomal chromosome (rather than a sex chromosome). The autosomal dominant muscular dystrophies are named according to the groups of affected muscles; FSHD affects muscles of the face, shoulders, and upper arms. FSHD may be especially benign, and many patients may be unaware of any symptoms. A variety of symptoms may be present in addition to muscular symptoms, and some researchers have considered the possibility that FSHD might be a heterogeneous collection of disorders. One of the symptoms which may accompany FSHD is neurosensory hearing loss. A study was therefore undertaken to evaluate the hearing in 56 patients from 9 FSHD families. Seventy-two healthy family members were also evaluated. Normally, the ability to hear a faint tone depends upon the pitch, or sound frequency, of the tone. When the hearing of the family members was evaluated, it was found that the differences between affected family members and controls were minimal. However, the fall-off in hearing as the tone increased in frequency from 4,000 to 6,000 Hz (hertz; cycles per second) was significantly greater among the patients. Although this fall-off is far from a significant hearing loss, these findings suggest that the cases of sensorimotor hearing loss associated with FSHD may simply represent the extreme end of a spectrum of effects on the auditory system. The demonstration of this hearing deficit in all families tested provides evidence that the underlying genetic cause is likely to be similar among all families with FSHD. (Consumer Summary produced by Reliance Medical Information, Inc.)

Two forms of muscular dystrophy (genetically determined conditions characterized by progressive muscle weakness and wasting) are Duchenne (inevitably fatal) and Becker muscular dystrophy, both of which are associated with the production of abnormal dystrophin. The dystrophin gene product in such cases is abnormally large. The function of this muscle protein is not known; to learn more about this issue, an animal model of dystrophy was investigated. Experiments were performed on muscle fibers from mice with different pedigrees with respect to the dystrophin gene. Muscle fibers from mice lacking dystrophin were more sensitive to sudden exposure to a hypo-osmotic bath (containing low concentrations of osmotically active substances), a reaction called osmotic shock, than fibers from control mice, dying within 12 minutes of exposure. This vulnerability was not seen in muscle fibers from mice with a different muscle disease (myotonia). Anatomical differences between dystrophic and control muscle fibers were also noted that indicated a history of extensive necrosis (cell death) and regeneration. Possible physiological events that could lead to cell death in the experimental system are discussed. It is possible that in Duchenne or Becker muscular dystrophy, relatively slight, but constant, reductions occur in the stability of the affected muscle fibers, leading to the abnormalities associated with the disorders. (Consumer Summary produced by Reliance Medical Information, Inc.)

In addition to showing differences in the levels of contractile proteins and metabolic enzymes, fast and slow muscles also differ in their expression profile of structural and synaptic proteins. Because utrophin is a structural protein expressed at the neuromuscular junction, we hypothesize that its expression may be different between fast and slow muscles. Western blots showed that, compared with fast extensor digitorum longus (EDL) muscles, slow soleus muscles contain significantly more utrophin. Quantitative RT-PCR revealed that this difference is accompanied by a parallel increase in the expression of utrophin transcripts. Interestingly, the higher levels of utrophin and its mRNA appear to occur in extrasynaptic regions of muscle fibers as shown by immunofluorescence and in situ hybridization experiments. Furthermore, nuclear run-on assays showed that the rate of transcription of the utrophin gene was nearly identical between EDL and soleus muscles, indicating that increased mRNA stability accounts for the higher levels of utrophin in slow muscles. Direct plasmid injections of reporter gene constructs showed that cis-acting elements contained within the utrophin 3'-untranslated region (3'-UTR) confer greater stability to chimeric LacZ transcripts in soleus muscles. Finally, we observed a clear difference between EDL and soleus muscles in the abundance of RNA-binding proteins interacting with the utrophin 3'-UTR. Together, these findings highlight the contribution of posttranscriptional events in regulating the expression of utrophin in muscle. Duchenne muscular dystrophy; synaptic proteins; messenger ribonucleic acid stability; ribonucleic acid-binding proteins; neuromuscular junction

Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the [Alpha]7[Beta]1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), [Alpha]2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and [Alpha]7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the [Alpha]7[Beta]1 integrin can compensate for the absence of dystrophin, we expressed the rat [Alpha]7 chain in mdx/[utr.sup.-/-] mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the [Alpha]7BX2 integrin chain was increased 2.0-2.3-fold in mdx/[utr.sup.-/-] mice. Concomitant with the increase in the [Alpha]7 chain, its heterodimeric partner, [Beta]1D, was also increased in the transgenic animals. Transgenic expression of the [Alpha]BX2 chain in the mdx/[utr.sup.-/-] mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering [Alpha]7[Beta]1 integrin--mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/[utr.sup.-/-] mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the [Alpha]7[Beta]1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/[utr.sup.-/-] and [Alpha]7BX2-mdx/[utr.sup.-/-] mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207. Key words: [Alpha]7[Beta]1 integrin * muscular dystrophy * dystrophin * utrophin * neuromuscular junction

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons of the spinal cord associated with muscle paralysis and caused by mutations of the survival motor neuron gene (SMN). To determine whether SMN gene defect in skeletal muscle might have a role in SMA pathogenesis, deletion of murine SMN exon 7, the most frequent mutation found in SMA, has been restricted to skeletal muscle by using the Cre-loxP system. Mutant mice display ongoing muscle necrosis with a dystrophic phenotype leading to muscle paralysis and death. The dystrophic phenotype is associated with elevated levels of creatine kinase activity, Evans blue dye uptake into muscle fibers, reduced amount of dystrophin and upregulation of utrophin expression suggesting a destabilization of the sarcolemma components. The mutant mice will be a valuable model for elucidating the underlying mechanism. Moreover, our results suggest a primary involvement of skeletal muscle in human SMA, which may contribute to motor defect in addition to muscle denervation caused by the motor neuron degeneration. These data may have important implications for the development of therapeutic strategies in SMA. Key words: spinal muscular atrophy * SMN * Cre-loxP * skeletal muscle * sarcolemma

Mutations in genes encoding for the sarcoglycans, a subset of proteins within the dystrophin-glycoprotein complex, produce a limb-girdle muscular dystrophy phenotype; however, the precise role of this group of proteins in the skeletal muscle is not known. To understand the role of the sarcoglycan complex, we looked for sarcoglycan interacting proteins with the hope of finding novel members of the dystrophin-glycoprotein complex. Using the yeast two-hybrid method, we have identified a skeletal muscle-specific form of filamin, which we term filamin 2 (FLN2), as a [Gamma]- and [Delta]-sarcoglycan interacting protein. In addition, we demonstrate that FLN2 protein localization in limb-girdle muscular dystrophy and Duchenne muscular dystrophy patients and mice is altered when compared with unaffected individuals. Previous studies of filamin family members have determined that these proteins are involved in actin reorganization and signal transduction cascades associated with cell migration, adhesion, differentiation, force transduction, and survival. Specifically, filamin proteins have been found essential in maintaining membrane integrity during force application. The finding that FLN2 interacts with the sarcoglycans introduces new implications for the pathogenesis of muscular dystrophy. Key words: dystrophin * muscular dystrophy * filamin C (FLNC) * cytoskeleton * cell signaling

Duchenne muscular dystrophy (DMD) is perhaps the most well known of the muscular dystrophies. Many of these syndromes, including DMD, are sex-linked disorders and the genes are located on the short arm (p) of the X chromosome. In addition, it appears that there are a number of familial muscle abnormalities which also map to the Xp21 region of the chromosome, but are not as insidious as DMD and are not progressive, as is DMD. A family has now been identified in which nine male members in two generations were affected with muscle cramps during normal exercise; a few individuals also experienced muscle pain, or myalgia. The second generation patients were born only to females of the first generation, which is strongly suggestive of an X-linked trait. The affected males had high levels of creatine kinase in their blood, and there was no sign of muscle weakness. The patients had well developed muscles, and hypertrophy (overdevelopment) of the muscles in the calves. Like DMD, the syndrome developed in childhood, but unlike DMD it did not progress. Examination of muscle biopsies showed indications of myopathy (muscle disease), but nothing which could be regarded as specific. The apparent linkage of this familial myopathy to the X chromosome prompted a molecular analysis of the genes for dystrophin, a protein associated with muscular dystrophy. It was found that there was a deletion in the dystrophin gene in these patients, that is, a portion of the gene was simply missing. Using antibodies to analyze the muscle specimens for the presence of dystrophin, researchers detected a normal quantity of dystrophin, but the molecules were abnormally small, as might result from a gene deletion. This strongly suggests that this gene is indeed responsible for the observed muscle-cramping syndrome. Furthermore, it indicates that a portion consisting of at least 15 percent of the dystrophin molecule may be missing without seriously affecting the molecule's function. (Consumer Summary produced by Reliance Medical Information, Inc.)

Thomas et al indicated that vasoactive nitric oxide (NO) can be produced by contracting muscle cells. The theory explained the manner by which skeletal muscle activity increased blood flow to supplement the heavy metabolic load. The research provided an important implication in understanding the pathophysiology and treatment of muscular diseases, particularly Duchenne muscular dystrophy. It was discovered that manipulation of NO levels in muscles can be a potential alternative in the treatment of muscular dystrophy.