Duchenne muscular dystrophy (DMD) is the most common sex linked lethal disease in man (one case in about 4000 male live births). The patients are wheelchair bound around the age of 8-10 years and usually die before the age of 20 years. The mutation rate, estimated by different methods and from different population studies, is in the order of 7 X 10(-5), which is higher than for any other X-linked genetic disease. Moreover, unlike other X linked diseases such as hemophilia A or Lesh-Nyhan's disease, there seems to be no sex difference for the mutation rates in DMD. Several observations of DMD in girls bearing X-autosomal translocations and linkage studies on two X chromosomal DNA restriction fragment length polymorphisms indicate that the DMD locus is situated on the short arm of the X chromosome, between Xp11 and Xp22. It may be of considerable length, and perhaps consisting of actively coding and non-active intervening DNA sequences. Thus unequal crossing over during meiosis in females could theoretically account for a considerable proportion of new mutations. However, there is no structurally or functionally abnormal protein known that might represent the primary gene product, nor has any pathogenetic mechanism leading to the observed biochemical and histological alterations been elucidated. Among the numerous pathogenetic concepts the hypothesis of a structural or/and functional defect of the muscular plasma membrane is still the most attractive. It would explain both the excess of muscular constituents found in serum of patients and carriers, such as creatine kinase (CK), as well as the excessive calcium uptake by dystrophic muscle fibres, which, prior to necrosis, could lead to hypercontraction, rupture of myofilaments in adjacent sarcomeres and by excessive Ca uptake to mitochondrial damage causing crucial energy loss. The results of studies on structural and functional membrane abnormalities in cells other than muscle tissue, e.g., erythrocytes, lymphocytes and cultured fibroblasts, indicate that the DMD mutation is probably demonstrable in these tissues. However, most of the findings are still difficult to reproduce or even controversial. DMD is an incurable disease; therefore most effort, in research as well as in practical medicine, is concentrated upon its prevention.(ABSTRACT TRUNCATED AT 400 WORDS)

Duchenne muscular dystrophy: pathogenetic aspects and genetic prevention.

In Duchenne muscular dystrophy, as in other genetic diseases, there must be a biochemical abnormality. This fundamental genetic fault has not been identified, but several indirect lines of evidence suggest that the surface membranes of skeletal muscle are affected. The biochemical evidence implies abnormal egress of soluble enzymes and other proteins from muscle, abnormal permeability, and altered properties of membrane-bound enzymes. As a result of the presumed genetic abnormality, functional properties are altered, and impaired regulation of intracellular calcium content could be responsible for the hallmarks of the disease--progressive weakness and degeneration of muscle. The evidence is by no means conclusive, however, and some of it is contradictory. Technical advances must be made before isolated membranes can be characterized biochemically. Other theories are also being evaluated.

Biochemistry of muscle membranes in Duchenne muscular dystrophy.

Recent advances in muscle biology concerning the discoveries of a large variety of proteins have been described in this review. The existence of polymorphism in several muscle proteins is now well established. Various isoforms of myosin not only account for the difference in physiological functions and biochemical activity of different fiber types or muscles, but also seem to differ in functional properties in food systems. The functionality of various muscle proteins, especially myosin and actin in the gelation process in modal systems which simulate structured meat products, is discussed at length. Besides, the role of different subunits and subfragments of myosin molecule in the gelation mechanism, and the various factors affecting heat-induced gelation of actomyosin in modal systems are also highlighted. Finally, the areas which need further investigation in this discipline have been suggested.

/pdf/recent-advances-in-meat-science-in-japan-functionality-of-3j4p6rwtzj.pdf

Recent Advances in Meat Science in Japan : Functionality of Muscle Proteins in Gelation Mechanisms of Structured Meat Products

Axis determination in eggs of Xenopus laevis: a critical period before first cleavage, identified by the common effects of cold, pressure and ultraviolet irradiation.

The muscle-specific intermediate filament protein, desmin, is one of the earliest myogenic markers whose functional role during myogenic commitment and differentiation is unknown. Sequence comparison of the presently isolated and fully characterized mouse desmin cDNA clones revealed a single domain of polypeptide similarity between desmin and the basic and helix-loop-helix region of members of the myoD family myogenic regulators. This further substantiated the need to search for the function of desmin. Constructs designed to express anti-sense desmin RNA were used to obtain stably transfected C2C12 myoblast cell lines. Several lines were obtained where expression of the anti-sense desmin RNA inhibited the expression of desmin RNA and protein down to basal levels. As a consequence, the differentiation of these myoblasts was blocked; complete inhibition of myoblast fusion and myotube formation was observed. Rescue of the normal phenotype was achieved either by spontaneous revertants, or by overexpression of the desmin sense RNA in the defective cell lines. In several of the cell lines obtained, inhibition of desmin expression was followed by differential inhibition of the myogenic regulators myoD and/or myogenin, depending on the stage and extent of desmin inhibition in these cells. These data suggested that myogenesis is modulated by at least more than one pathway and desmin, which so far was believed to be merely an architectural protein, seems to play a key role in this process.

/pdf/inhibition-of-desmin-expression-blocks-myoblast-fusion-and-4bs7zcccze.pdf

Inhibition of desmin expression blocks myoblast fusion and interferes with the myogenic regulators MyoD and myogenin

Most eukaryotic cells possess three major distinct classes of fibrous organelles that are independently organized and function as elements of the cytoskeleton. These elements of the cytoskeleton include microtubules (25 nm), which form elaborate cytoplasmic networks; actin or thin filaments (6 nm), which form cytoplasmic stress fibers; and the intermediate filaments (10 nm). The term “intermediate” filaments has been applied to this third class of cytoplasmic fibrous proteins because their mean diameter at the ultrastructural level lies between the mean diameter of actin and microtubules. Investigations have shown that both actin (Clarke and Spudeck, 1977; Pollard and Werhing, 1974; Stossel, 1978) and microtubules (Stephens and Edds, 1976) are involved in various aspects of cell motility and also in the movement of cellular organelles. The role of the intermediate filaments in cell function is unresolved at present. The intermediate filaments were initially regarded as a disaggregation, or degradation product, or myosin and/or microtubules and thus until recently attracted little attention. Current biochemical and immunofluorescent methods have established the intermediate filaments as a distinct class of cytoplasmic proteins that differ with respect to the physical properties of their subunits. In contrast to the proteins actin and tubulin, which are the major structural protein subunits of microfilaments and microtubules, respectively, the intermediate-filament proteins do not appear to be highly conserved (Bennett et al., 1979; Lazarides and Balzer, 1978; Shelanski and Liem, 1979) and exhibit a relatively high degree of tissue specificity. The intermediate filaments have been divided into several subclasses on the basis of biochemical and immunochemical data, and their constituent proteins have been named accordingly. These subclasses at present include: (1) prekeratin tonofilaments found in epithelial cells (Franke et al.,1978a,b, 1979b; Sun et al., 1979) and cells of epithelial origin; (2) vimentin or decamin filaments (Bennett et al., 1978b, 1979; Franke et al.,1978a, 1979a) found in fibroblasts and other cells of mesenchymal orgin; (3) desmin filaments (Izant and Lazarides, 1974; Lazarides and Hubbard, 1976; Lazarides, 1978a; Lazarides and Balzer, 1978) or skeletin (Campbell et al.,1979) of smooth muscle, which have also been identified in the cytoplasm and Z lines of skeletal and cardiac muscle; (4) neurofilaments of neurons; and (5) glial filaments, which are present in astrocytes (Shelanski and Liem, 1979) but not in all types of glial cells (Liem et al., 1978; Schlaepfer, 1977; Schlaepfer and Lynch, 1977). Current studies have shown that it is not uncommon to find two of these classes of intermediate filaments coexisting in the same cell type. It is also quite possible that more than two classes of intermediate filaments can be present in a single cell type (Lazarides, 1980).

The Role of Intermediate (10-nm) Filaments in the Development and Integration of the Myofibrillar Contractile Apparatus in the Embryonic Mammalian Heart

Microtubules and Duchenne muscular dystrophy.

Since there is at present no effective form of chemotherapy available to humans affected with the major types of muscular dystrophy, hereditary and experimentally induced animal models have been extensively studied to gain information about beneficial effects of various pharmacological agents and to study nerve-muscle interactions with respect to structure and function. None of the animal models, however, is directly comparable to any of the human dystrophies, and analogies drawn between them can be very misleading. However, the genetically dystrophic chicken provides a convenient model for testing drugs that may be of benefit even though the primary lesions in these animals are unknown and their relevance to human muscular dystrophies is unclear. Despite these drawbacks, the dystrophic-chicken model is an especially promising system for the study of genetically inherited myopathies because the progressive developmental onset of the disease closely mimics the human form of Duchenne muscular dystrophy in the areas of histological signs of muscle degeneration, muscle-enzyme leakage into blood, and progressive loss of functional ability. Because of the large number of similarities that the avian model of muscular dystrophy shares with Duchenne muscular dystrophy, chemotherapeutic trials in chickens can assess quantitative and qualitative parameters before clinical trials are initiated. In this chapter, both morphological and biochemical data will be presented to document a cyto-skeletal defect in avian muscular dystrophy. Isaxonine, a recently synthesized drug, retards the developmental pathological processes in the dystrophic chicken. It will be shown that by daily injection of this chemotherapeutic agent, the cytoskeletal defect in avian muscular dystrophy is corrected.

Cytoskeletal Defects in Avian Muscular Dystrophy

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The Role of Intermediate (10-nm) Filaments in the Development and Integration of the Myofibrillar Contractile Apparatus in the Embryonic Mammalian Heart

Microtubules and Duchenne muscular dystrophy.

Cytoskeletal Defects in Avian Muscular Dystrophy