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Our trails and trials in the subsarcolemmal cytoskeleton network and muscular dystrophy researches in the dystrophin era.

Ozawa E - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Bottom Line: After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD.Our prediction was confirmed to be true by many researchers including ourselves.In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.

View Article: PubMed Central - PubMed

Affiliation: National Center of Neuroscience, NCNP, Kodairashi, Tokyo 187-8502, Japan. ozawa@ncnp.go.jp

ABSTRACT
In 1987, about 150 years after the discovery of Duchenne muscular dystrophy (DMD), its responsible gene, the dystrophin gene, was cloned by Kunkel. This was a new substance. During these 20 odd years after the cloning, our understanding on dystrophin as a component of the subsarcolemmal cytoskeleton networks and on the pathomechanisms of and experimental therapeutics for DMD has been greatly enhanced. During this paradigm change, I was fortunately able to work as an active researcher on its frontiers for 12 years. After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD. During the conduct of these studies, we came to consider that the dystrophin-DAP complex serves to transmembranously connect the subsarcolemmal cytoskeleton networks and basal lamina to protect the lipid bilayer. It then became our working hypothesis that injury of the lipid bilayer upon muscle contraction is the cause of DMD. During this process, we predicted that subunits of the sarcoglycan (SG) complex are responsible for respective types of DMD-like muscular dystrophy with autosomal recessive inheritance. Our prediction was confirmed to be true by many researchers including ourselves. In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.

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Transverse fixation system (TFS). A. Molecular architecture of TFS: DVIF that surrounds and fixes many myofibrils (mf) at the Z-band level and radiates outward to the sarcolemma. Roughly, desmin in the DIVF connects to actin filament in the subsarcolemmal cytoskeleton networks via plectin, then to the dystrophin bolt which is finally fixed to the basal lamina. It also connected to dystrobrevin via syncoilin and/or β-synemin that bind to the C-terminal domain of dystrophin, which is finally fixed to the basal lamina via dystroglycan. PL, plectin; S, syncoilin and/or β-synemin; lam, laminin. For other abbreviations see Table 1. B. Function of TFS: Festooning of the sarcolemma upon contraction observed in longitudinal section (B-b). a, relaxation; b, contraction; and c, relaxation. Red bar on the lipid bilayer indicates the dystrophin bolt. Arrow in b: flux of cytoplasm toward sarcolemma upon contraction. Note that the sarcolemma balloons upon contraction owing to the flux of the cytoplasm from the core of the muscle fiber. However, at costameres, which are moored to the myofibrils by TFS, the sarcolemma retracts. The ballooning of the sarcolemma becomes flat upon relaxation. For further details see the text.
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fig06: Transverse fixation system (TFS). A. Molecular architecture of TFS: DVIF that surrounds and fixes many myofibrils (mf) at the Z-band level and radiates outward to the sarcolemma. Roughly, desmin in the DIVF connects to actin filament in the subsarcolemmal cytoskeleton networks via plectin, then to the dystrophin bolt which is finally fixed to the basal lamina. It also connected to dystrobrevin via syncoilin and/or β-synemin that bind to the C-terminal domain of dystrophin, which is finally fixed to the basal lamina via dystroglycan. PL, plectin; S, syncoilin and/or β-synemin; lam, laminin. For other abbreviations see Table 1. B. Function of TFS: Festooning of the sarcolemma upon contraction observed in longitudinal section (B-b). a, relaxation; b, contraction; and c, relaxation. Red bar on the lipid bilayer indicates the dystrophin bolt. Arrow in b: flux of cytoplasm toward sarcolemma upon contraction. Note that the sarcolemma balloons upon contraction owing to the flux of the cytoplasm from the core of the muscle fiber. However, at costameres, which are moored to the myofibrils by TFS, the sarcolemma retracts. The ballooning of the sarcolemma becomes flat upon relaxation. For further details see the text.

Mentions: [1] The dystrophin bolt functions in two ways: First, the dystrophin bolt stitching the sarcolemma is diffusely distributed throughout the sarcolemma, as explained in Discussion (2) (Fig. 2 & 3B). Second, densely located at the costameres, it also serves as a part of larger structure that links the Z-bands of myofibrils and the basal lamina (Fig. 6A).51,83) Desmin–vimentin intermediate filaments (DVIF)84) wind around individual myofibrils at the level of each Z-band fixing all myofibrils together to form a myofibril bundle. These DVIF further radiate away from the myofibrils to the costamere, a condensed portion of the subsarcolemmal cytoskeleton networks, where DVIF indirectly connect to the dystrophin bolt. This system was named the transverse fixation system (TFS),37) details of which were described elsewhere.51) Thus, I understood that the dystrophin bolt was a missing link of TFS that transmembranously connects the DVIF and the basal lamina.


Our trails and trials in the subsarcolemmal cytoskeleton network and muscular dystrophy researches in the dystrophin era.

Ozawa E - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Transverse fixation system (TFS). A. Molecular architecture of TFS: DVIF that surrounds and fixes many myofibrils (mf) at the Z-band level and radiates outward to the sarcolemma. Roughly, desmin in the DIVF connects to actin filament in the subsarcolemmal cytoskeleton networks via plectin, then to the dystrophin bolt which is finally fixed to the basal lamina. It also connected to dystrobrevin via syncoilin and/or β-synemin that bind to the C-terminal domain of dystrophin, which is finally fixed to the basal lamina via dystroglycan. PL, plectin; S, syncoilin and/or β-synemin; lam, laminin. For other abbreviations see Table 1. B. Function of TFS: Festooning of the sarcolemma upon contraction observed in longitudinal section (B-b). a, relaxation; b, contraction; and c, relaxation. Red bar on the lipid bilayer indicates the dystrophin bolt. Arrow in b: flux of cytoplasm toward sarcolemma upon contraction. Note that the sarcolemma balloons upon contraction owing to the flux of the cytoplasm from the core of the muscle fiber. However, at costameres, which are moored to the myofibrils by TFS, the sarcolemma retracts. The ballooning of the sarcolemma becomes flat upon relaxation. For further details see the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037518&req=5

fig06: Transverse fixation system (TFS). A. Molecular architecture of TFS: DVIF that surrounds and fixes many myofibrils (mf) at the Z-band level and radiates outward to the sarcolemma. Roughly, desmin in the DIVF connects to actin filament in the subsarcolemmal cytoskeleton networks via plectin, then to the dystrophin bolt which is finally fixed to the basal lamina. It also connected to dystrobrevin via syncoilin and/or β-synemin that bind to the C-terminal domain of dystrophin, which is finally fixed to the basal lamina via dystroglycan. PL, plectin; S, syncoilin and/or β-synemin; lam, laminin. For other abbreviations see Table 1. B. Function of TFS: Festooning of the sarcolemma upon contraction observed in longitudinal section (B-b). a, relaxation; b, contraction; and c, relaxation. Red bar on the lipid bilayer indicates the dystrophin bolt. Arrow in b: flux of cytoplasm toward sarcolemma upon contraction. Note that the sarcolemma balloons upon contraction owing to the flux of the cytoplasm from the core of the muscle fiber. However, at costameres, which are moored to the myofibrils by TFS, the sarcolemma retracts. The ballooning of the sarcolemma becomes flat upon relaxation. For further details see the text.
Mentions: [1] The dystrophin bolt functions in two ways: First, the dystrophin bolt stitching the sarcolemma is diffusely distributed throughout the sarcolemma, as explained in Discussion (2) (Fig. 2 & 3B). Second, densely located at the costameres, it also serves as a part of larger structure that links the Z-bands of myofibrils and the basal lamina (Fig. 6A).51,83) Desmin–vimentin intermediate filaments (DVIF)84) wind around individual myofibrils at the level of each Z-band fixing all myofibrils together to form a myofibril bundle. These DVIF further radiate away from the myofibrils to the costamere, a condensed portion of the subsarcolemmal cytoskeleton networks, where DVIF indirectly connect to the dystrophin bolt. This system was named the transverse fixation system (TFS),37) details of which were described elsewhere.51) Thus, I understood that the dystrophin bolt was a missing link of TFS that transmembranously connects the DVIF and the basal lamina.

Bottom Line: After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD.Our prediction was confirmed to be true by many researchers including ourselves.In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.

View Article: PubMed Central - PubMed

Affiliation: National Center of Neuroscience, NCNP, Kodairashi, Tokyo 187-8502, Japan. ozawa@ncnp.go.jp

ABSTRACT
In 1987, about 150 years after the discovery of Duchenne muscular dystrophy (DMD), its responsible gene, the dystrophin gene, was cloned by Kunkel. This was a new substance. During these 20 odd years after the cloning, our understanding on dystrophin as a component of the subsarcolemmal cytoskeleton networks and on the pathomechanisms of and experimental therapeutics for DMD has been greatly enhanced. During this paradigm change, I was fortunately able to work as an active researcher on its frontiers for 12 years. After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD. During the conduct of these studies, we came to consider that the dystrophin-DAP complex serves to transmembranously connect the subsarcolemmal cytoskeleton networks and basal lamina to protect the lipid bilayer. It then became our working hypothesis that injury of the lipid bilayer upon muscle contraction is the cause of DMD. During this process, we predicted that subunits of the sarcoglycan (SG) complex are responsible for respective types of DMD-like muscular dystrophy with autosomal recessive inheritance. Our prediction was confirmed to be true by many researchers including ourselves. In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.

Show MeSH
Related in: MedlinePlus