Increase of muscle mitochondrial content with age in murine muscular dystrophy

Comparison of morphological features of gastrocnemius muscle fibers in normal and dystrophic (dy^2J) mice during development was undertaken to determine the time course of increased oxidative capacity in dystrophic fibers. Measurements of mitochondrial volume percent and of Z-line width were made in superficial fast-twitch fibers using electron microscopy and stereological techniques. Dystrophic fibers develop a progressively higher mitochondrial volume percent than normal fibers after 1 month of age. Z-line width is positively correlated with mitochondrial volume percent. The results support the hypothesis that progressive changes in muscle fiber properties result from abnormal neural activity (pseudomyotonia) in dystrophic animals.     

Possible neurogenic factor in muscular dystrophy: its similarity to denervation atrophy

Muscle biopsy specimens from 179 cases of muscular dystrophies and from 140 cases of anterior horn cell disorders (from a total of 1,348 biopsied patients) were examined histologically. There were 72 cases of Duchenne type muscular dystrophy (DMD), five of Becker type MD, four girls with myopathy resembling DMD, 40 with limb-girdle, 10 with facioscapulohumeral, seven with late onset, 13 with congenital, and 28 with unclassifiable muscular dystrophies. Groups of small atrophied muscle fibres were encountered in 42 (23%) of the cases in this group, most frequently in patients with limb-girdle, facioscapulohumeral, and least frequently with DM dystrophy. In the second group there were 25 cases of infantile, 38 of juvenile, and 39 of adult spinal muscular atrophy (SMA); there were 21 patients with motor neurone disease (MND), six with poliomyelitis, and 11 with an unclassifiable type of anterior horn cell disorder. Pseudomyopathic changes were encountered in 43 (30%) of all cases in this group. They were most frequently present among patients with juvenile and adult SMA and in those with MND. The presence of group atrophy in muscular dystrophy is considered significant myopathological evidence of a denervation process. On the other hand, pseudomyopathic changes, variation in fibre size, rounding, central nuclei, and increase in connective tissue occurring in various anterior horn cell disorders are seen not to be specific `myopathic'' changes. Thus there was an overlap of pathological reactions in muscles from the dystrophies and the neurogenic atrophies. Comparably atrophied fibres (much less than 2 SDs below the normal mean diameter) and hypertrophied fibres (much more than 2 SDs above the normal mean diameter) were encountered in both dystrophy and neurogenic atrophy, considering the large muscles of the limb. Likewise, the mean fibre diameters were comparable in DMD and in juvenile SMA. The fourth evidence of a neurogenic factor in muscular dystrophy was derived from an examination of SDH preparations of muscle. There was a preponderance of type I muscle fibres in dystrophic muscles compared with specimens from controls, suggesting depletion of type II fibres. It appears that the concept of muscular dystrophy as a primary muscle disease needs to be re-examined.     

Gene expression profiling of Duchenne muscular dystrophy skeletal muscle

The primary cause of Duchenne muscular dystrophy (DMD) is a mutation in the dystrophin gene, leading to absence of the corresponding protein, disruption of the dystrophin-associated protein complex, and substantial changes in skeletal muscle pathology. Although the primary defect is known and the histological pathology well documented, the underlying molecular pathways remain in question. To clarify these pathways, we used expression microarrays to compare individual gene expression profiles for skeletal muscle biopsies from DMD patients and unaffected controls. We have previously published expression data for the 12,500 known genes and full-length expressed sequence tags (ESTs) on the Affymetrix HG-U95Av2 chips. Here we present comparative expression analysis of the 50,000 EST clusters represented on the remainder of the Affymetrix HG-U95 set. Individual expression profiles were generated for biopsies from 10 DMD patients and 10 unaffected control patients. Two methods of statistical analysis were used to interpret the resulting data (t-test analysis to determine the statistical significance of differential expression and geometric fold change analysis to determine the extent of differential expression). These analyses identified 183 probe sets (59 of which represent known genes) that differ significantly in expression level between unaffected and disease muscle. This study adds to our knowledge of the molecular pathways that are altered in the dystrophic state. In particular, it suggests that signaling pathways might be substantially involved in the disease process. It also highlights a large number of unknown genes whose expression is altered and whose identity therefore becomes important in understanding the pathogenesis of muscular dystrophy. Electronic Supplementary Material Supplementary material is available for this article if you access the article at . A link in the frame on the left on that page takes you directly to the supplementary material.     

Familial facioscapulohumeral muscular dystrophy: phenotypic diversity and genetic abnormality

We report two cases showing facioscapulohumeral muscular dystrophy (FSHD) with phenotypic diversity but the same genetic abnormality detected by a p13E-11 probe. The proband, a 26-year-old woman, showed an early onset, tortuosity of retinal arterioles and respiratory failure. The 53-year-old mother of the proband had limb-girdle (L-G) type muscular weakness with very mild facial involvement. Muscle biopsy showed perivascular cell infiltration in both patients. These cases suggest that the phenotypic diversity ranges from L-G type weakness to severe respiratory failure in FSHD family.     

Ultrasound imaging of the muscle in muscular dystrophy

Ultrasound imaging of muscle was performed on 40 patients of Duchenne muscular dystrophy on lower and upper extremities. In the control subjects, there was good visualization of bone and fascia with echo-free muscle tissue. With progression of the disease, the muscle echo was increased with corresponding loss of fascia echo in muscular dystrophy. A few advanced cases showed relatively echo-free muscle because of diffuse adipose tissue infiltration. Ultrasound imaging can reveal the muscular lesion and its distribution, and is valuable for monitoring the progression of the disease.     

Permanent muscular sodium overload and persistent muscle edema in Duchenne muscular dystrophy: a possible contributor of progressive muscle degeneration

To assess the presence and persistence of muscular edema and increased myoplasmic sodium (Na⁺) concentration in Duchenne muscular dystrophy (DMD). We examined eight DMD patients (mean age 9.5?±?5.4?years) and eight volunteers (mean age 9.5?±?3.2?years) with 3-tesla proton (¹H) and ²³Na density-adapted 3D-radial MR sequences. Seven DMD patients were re-examined about 7?months later without change of therapy. The eighth DMD patient was re-examined after 5 and 11?months under medication with eplerenone. We quantified muscle edema on STIR images with background noise as reference and fatty degeneration on T1-weighted images using subcutaneous fat as reference. Na⁺ was quantified by a muscular tissue Na⁺ concentration (TSC) sequence employing a reference containing 51.3?mM Na⁺ with 5?% agarose. With an inversion-recovery (IR) sequence, we determined mainly the myoplasmic Na⁺. The normalized muscular ²³Na IR signal intensity was higher in DMD than in volunteers (n?=?8, 0.75?±?0.07 vs. 0.50?±?0.05, p?<?0.001) and persisted at second measurement (n?=?7, 1st 0.75?±?0.07, 2nd 0.73?±?0.06, p?=?0.50). When compared to volunteers (25.6?±?2.0?mmol/l), TSC was markedly increased in DMD (38.0?±?5.9?mmol/l, p?<?0.001) and remained constant (n?=?7, 1st 37.9?±?6.4?mmol/l, 2nd 37.0?±?4.0?mmol/l, p?=?0.49). Muscular edema (15.6?±?3.5 vs. 6.9?±?0.7, p?<?0.001) and fat content (0.48?±?0.08 vs. 0.38?±?0.01, p?=?0.003) were elevated in DMD when compared to volunteers. This could also be confirmed during follow-up (n?=?7, p?=?0.91, p?=?0.12). Eplerenone slightly improved muscle strength and reduced muscular sodium and edema. The permanent muscular Na⁺ overload in all DMD patients is likely osmotically relevant and responsible for the persisting, mainly intracellular muscle edema that may contribute to the progressive muscle degeneration.     

Probabilistic muscle characterization using quantitative electromyography: Application to facioscapulohumeral muscular dystrophy

Based on quantitative electromyography, a muscle can be categorized as normal or affected by a neuromuscular disorder. The objective of this work was to compare the utility of probabilistic to conventional means and outlier methods of categorization of myopathic and normal muscles. Various sets of motor unit potential (MUP) features detected in biceps brachii muscles of control subjects and patients with facioscapulohumeral muscular dystrophy were used to categorize them as normal or myopathic based on conventional means and outlier categorization (CMC) as well as a new probabilistic muscle categorization (PMC). The sensitivity, specificity, and accuracy provided by each categorization method were compared. The categorizations made using PMC were significantly more accurate (by at least 10%) compared with CMC (P < 10^?10) for muscles evaluated in this study. Area, duration, and thickness were highly discriminative MUP features. Muscle Nerve, 2010     

Spinal motor neurones in murine muscular dystrophy and spinal muscular atrophy: A quantitative histological study

Recent electrophysiological studies of human and mouse muscular dystrophy have prompted the hypothesis that both are of neurogenic rather than myogenic origin. A decreased number of spinal motor neurones might be expected if this hypothesis were correct. The total number of neurones in the anterior grey horns of seven normal mice, six Bar Harbor 129 strain dystrophic mice, and six mice suffering from genetically-determined spinal muscular atrophy have been counted. The number of neurones in the cell types believed to include the motor neurones was significantly reduced to 13 to 71% of normal in mice with spinal muscular atrophy. In mice with muscular dystrophy, the number of anterior horn neurones was higher rather than lower than normal. The significance of these findings is discussed.     

Sex differences in the phenotypic expression of avian dystrophy

Although the gene for muscular dystrophy in chickens is not sex-linked, results from clinical tests suggest that it is expressed differently in males and females. As measurement of muscle contractile responses provides a quantitative index for the severity of the disease, the contractile properties of the extensor digitorum communis muscle were examined in normal and dystrophic chickens with respect to sex. Furthermore, these differences were examined in young (6 to 9 weeks) and old (greater than 6 months) chickens. Results showed that age-related sex differences were apparent for those mechanical parameters of the muscle (in particular the posttetanic potentiation and posttetanic contracture) known to distinguish normal and dystrophic birds. The sex differences observed in the younger group indicate that the female birds were more severely affected by the disease than were the male. In the older group, the male were affected by the disease more severely than age-matched female birds. If the inheritance pattern is truly autosomal then it is likely that one or more developmental factors interact with the dystrophic genotype and alter the dystrophic phenotype.     

Successful treatment of murine muscular dystrophy with the protease inhibitor bestatin

Continued administration of the dipeptide protease inhibitor Bestatin to 34 mice with genetic muscular dystrophy from the onset of clinical deficit, cured about half of the animals within 3 months. Cessation of treatment in the recovered mice at age 4 months was not followed by relapse. Examinations of these mice revealed recovery of (1) weight gain and life span, (2) muscle strength, and (3) marker enzyme activities in skeletal muscle and serum, as well as (4) disappearance of myopathological features characteristic of the disease such as necrosis of muscle fibers, centralization or a chain like arrangement of nuclei, or a marked infiltration of collagenous fibers. Finally, (5) the genetic confirmation of the animals which attained remission was confirmed to be dy/dy.     

Delayed expression of dystrophin on regenerating muscle from two siblings with Becker muscular dystrophy

We present here a unique expression of dystrophin on biopsied muscle from 2 siblings with Becker muscular dystrophy (BMD). They had neither muscle weakness nor atrophy. Clustered dystrophin-deficient fibers were constituted to regenerating basophilic fibers (mainly type 2C fiber) based on histochemical stainings. We speculate that the developmental delay in the expression of dystrophin is a characteristics finding in regenerating fibers from asymptomatic and young BMD patients, such as the siblings in this report.     

Real-time sonography of acute and chronic muscle denervation

Presented are real-time ultrasound findings in partially and completely denervated muscles of 30 patients with focal neuropathy and various other disorders of the second motor neuron. Sonographic scans of affected muscles are analyzed in conjunction with unaffected muscles of the same individual, under identical examination conditions. Initial pathological ultrasound changes could be detected as soon as 2 weeks after an acute neurogenic lesion. In denervation, the echodensity of the muscle was high and the normal intramuscular pattern was decomposed. Findings were more intense in severe and longstanding denervation. Ultrasound-indicated pathology correlated highly (chi-square: P less than 0.001) with pathological spontaneous activity detected by electromyography. Focal and systemic neuropathies showed no differences in ultrasound pathology. Six cases with central motor palsy had normal sonograms. Poor spatial resolution of real-time ultrasonography--as compared with CT and MRI--is compensated by its bedside availability, frequent repeatability without patient risk and discomfort, and its in vivo correlation of muscle morphology with muscle function.     

Cytogenetic analysis and muscle differentiation in a girl with severe muscular dystrophy

Summary The uncommon case is described of a girl severely affected with Duchenne muscular dystrophy. Cytogenetic analysis revealed no numerical or structural abnormalities of the X-chromosome in any of the cells examined (leucocytes and myoblasts). No abnormality in morphology, growth pattern or differentiation was observed in the dystrophic muscle cultures as compared with control cultures.Supported in part by MPI Research Project and by Legato Dino Ferrari, Modena, Italy