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Sorting of a nonmuscle tropomyosin to a novel cytoskeletal compartment in skeletal muscle results in muscular dystrophy.

Kee AJ, Schevzov G, Nair-Shalliker V, Robinson CS, Vrhovski B, Ghoddusi M, Qiu MR, Lin JJ, Weinberger R, Gunning PW, Hardeman EC - J. Cell Biol. (2004)

Bottom Line: Tropomyosin (Tm) is a key component of the actin cytoskeleton and >40 isoforms have been described in mammals.These isoforms are excluded from the thin filament of the sarcomere and are localized to a novel Z-line adjacent structure.Our findings raise the possibility that mutations in these tropomyosin and these structures may underpin these types of myopathies.

View Article: PubMed Central - PubMed

Affiliation: Muscle Development Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, New South Wales 2145, Australia.

ABSTRACT
Tropomyosin (Tm) is a key component of the actin cytoskeleton and >40 isoforms have been described in mammals. In addition to the isoforms in the sarcomere, we now report the existence of two nonsarcomeric (NS) isoforms in skeletal muscle. These isoforms are excluded from the thin filament of the sarcomere and are localized to a novel Z-line adjacent structure. Immunostained cross sections indicate that one Tm defines a Z-line adjacent structure common to all myofibers, whereas the second Tm defines a spatially distinct structure unique to muscles that undergo chronic or repetitive contractions. When a Tm (Tm3) that is normally absent from muscle was expressed in mice it became associated with the Z-line adjacent structure. These mice display a muscular dystrophy and ragged-red fiber phenotype, suggestive of disruption of the membrane-associated cytoskeletal network. Our findings raise the possibility that mutations in these tropomyosin and these structures may underpin these types of myopathies.

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Related in: MedlinePlus

Exon composition of tropomyosin (Tm) isoforms. The α-TM (A), β-TM (B), and γ-TM (C) gene organization is shown, with boxes representing exons, lines introns, and unshaded parts of the exons untranslated regions. Homologous exons of the three genes are shown in the same shading pattern. Constitutive exons that are present in all known isoforms are represented by solid black boxes. A vertical bar and the letter A represent alternate polyadenylation sites. Antibodies used in this study with the specific exons they detect are shown in italics on the gene maps. All possible isoforms from the three genes are not depicted. The 311 antibody detects all isoforms containing exon 1a which includes sarcomeric (αTmfast, βTm, and αTmslow) and NS Tms, and the α9d antibody detects 9d containing isoforms from the α-TM and β-TM genes. The γ-TM gene-specific antibodies CG3 and γ9d recognize isoforms containing exons 1b and 9d, respectively.
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fig1: Exon composition of tropomyosin (Tm) isoforms. The α-TM (A), β-TM (B), and γ-TM (C) gene organization is shown, with boxes representing exons, lines introns, and unshaded parts of the exons untranslated regions. Homologous exons of the three genes are shown in the same shading pattern. Constitutive exons that are present in all known isoforms are represented by solid black boxes. A vertical bar and the letter A represent alternate polyadenylation sites. Antibodies used in this study with the specific exons they detect are shown in italics on the gene maps. All possible isoforms from the three genes are not depicted. The 311 antibody detects all isoforms containing exon 1a which includes sarcomeric (αTmfast, βTm, and αTmslow) and NS Tms, and the α9d antibody detects 9d containing isoforms from the α-TM and β-TM genes. The γ-TM gene-specific antibodies CG3 and γ9d recognize isoforms containing exons 1b and 9d, respectively.

Mentions: The large diversity of tropomyosin isoforms results from multiple promoter initiation sites and extensive alternate splicing from four genes (isoforms from three genes are shown in Fig. 1). We and others have developed antibodies that detect a large variety of NS tropomyosins from the TM genes (Fig. 1). These antibodies were raised against peptides encoded by specific exons, most of which recognize gene-specific products (e.g., γ9d). Using these antibodies, it has been established in nonmuscle cells that the repertoire of Tms expressed is both cell-type specific, and spatially segregated within a cell (Lin et al., 1997; Gunning et al., 1998a,b). We have previously observed that after muscle differentiation, at least one mRNA encoding a cytoskeletal Tm from the γ-TM gene persists in adult muscle. Antibodies directed against the amino- (CG3) and carboxy-terminal (γ9d) exons of the γ-TM gene were used to define protein expression and location in adult muscle (Fig. 1).


Sorting of a nonmuscle tropomyosin to a novel cytoskeletal compartment in skeletal muscle results in muscular dystrophy.

Kee AJ, Schevzov G, Nair-Shalliker V, Robinson CS, Vrhovski B, Ghoddusi M, Qiu MR, Lin JJ, Weinberger R, Gunning PW, Hardeman EC - J. Cell Biol. (2004)

Exon composition of tropomyosin (Tm) isoforms. The α-TM (A), β-TM (B), and γ-TM (C) gene organization is shown, with boxes representing exons, lines introns, and unshaded parts of the exons untranslated regions. Homologous exons of the three genes are shown in the same shading pattern. Constitutive exons that are present in all known isoforms are represented by solid black boxes. A vertical bar and the letter A represent alternate polyadenylation sites. Antibodies used in this study with the specific exons they detect are shown in italics on the gene maps. All possible isoforms from the three genes are not depicted. The 311 antibody detects all isoforms containing exon 1a which includes sarcomeric (αTmfast, βTm, and αTmslow) and NS Tms, and the α9d antibody detects 9d containing isoforms from the α-TM and β-TM genes. The γ-TM gene-specific antibodies CG3 and γ9d recognize isoforms containing exons 1b and 9d, respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172434&req=5

fig1: Exon composition of tropomyosin (Tm) isoforms. The α-TM (A), β-TM (B), and γ-TM (C) gene organization is shown, with boxes representing exons, lines introns, and unshaded parts of the exons untranslated regions. Homologous exons of the three genes are shown in the same shading pattern. Constitutive exons that are present in all known isoforms are represented by solid black boxes. A vertical bar and the letter A represent alternate polyadenylation sites. Antibodies used in this study with the specific exons they detect are shown in italics on the gene maps. All possible isoforms from the three genes are not depicted. The 311 antibody detects all isoforms containing exon 1a which includes sarcomeric (αTmfast, βTm, and αTmslow) and NS Tms, and the α9d antibody detects 9d containing isoforms from the α-TM and β-TM genes. The γ-TM gene-specific antibodies CG3 and γ9d recognize isoforms containing exons 1b and 9d, respectively.
Mentions: The large diversity of tropomyosin isoforms results from multiple promoter initiation sites and extensive alternate splicing from four genes (isoforms from three genes are shown in Fig. 1). We and others have developed antibodies that detect a large variety of NS tropomyosins from the TM genes (Fig. 1). These antibodies were raised against peptides encoded by specific exons, most of which recognize gene-specific products (e.g., γ9d). Using these antibodies, it has been established in nonmuscle cells that the repertoire of Tms expressed is both cell-type specific, and spatially segregated within a cell (Lin et al., 1997; Gunning et al., 1998a,b). We have previously observed that after muscle differentiation, at least one mRNA encoding a cytoskeletal Tm from the γ-TM gene persists in adult muscle. Antibodies directed against the amino- (CG3) and carboxy-terminal (γ9d) exons of the γ-TM gene were used to define protein expression and location in adult muscle (Fig. 1).

Bottom Line: Tropomyosin (Tm) is a key component of the actin cytoskeleton and >40 isoforms have been described in mammals.These isoforms are excluded from the thin filament of the sarcomere and are localized to a novel Z-line adjacent structure.Our findings raise the possibility that mutations in these tropomyosin and these structures may underpin these types of myopathies.

View Article: PubMed Central - PubMed

Affiliation: Muscle Development Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, New South Wales 2145, Australia.

ABSTRACT
Tropomyosin (Tm) is a key component of the actin cytoskeleton and >40 isoforms have been described in mammals. In addition to the isoforms in the sarcomere, we now report the existence of two nonsarcomeric (NS) isoforms in skeletal muscle. These isoforms are excluded from the thin filament of the sarcomere and are localized to a novel Z-line adjacent structure. Immunostained cross sections indicate that one Tm defines a Z-line adjacent structure common to all myofibers, whereas the second Tm defines a spatially distinct structure unique to muscles that undergo chronic or repetitive contractions. When a Tm (Tm3) that is normally absent from muscle was expressed in mice it became associated with the Z-line adjacent structure. These mice display a muscular dystrophy and ragged-red fiber phenotype, suggestive of disruption of the membrane-associated cytoskeletal network. Our findings raise the possibility that mutations in these tropomyosin and these structures may underpin these types of myopathies.

Show MeSH
Related in: MedlinePlus