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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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In transverse section, the γ9d Tms localize with a γ-actin, whereas the CG3 Tms do not. Shown are confocal images of transverse sections (7 μm) through soleus muscles stained with γ9d (A) or CG3 (D) and costained with a γ-actin antibody (B and E). The merged images show that the Tms recognized by γ9d colocalize with a γ-actin within the myofiber and at the fiber periphery (C), whereas the CG3 Tms are not localized with γ-actin (F). In addition, signal for a γ-actin did not coincide with α-actinin (I, enlarged inset) indicating that γ-actin microfilaments are not closely associated with the myofibrils. The most intense γ-actin staining was at the myofiber periphery (B, E, H, and K), but the staining was mostly distinct from the sarcolemmal staining of dystrophin (L, inset). Bars, 20 μm.
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fig6: In transverse section, the γ9d Tms localize with a γ-actin, whereas the CG3 Tms do not. Shown are confocal images of transverse sections (7 μm) through soleus muscles stained with γ9d (A) or CG3 (D) and costained with a γ-actin antibody (B and E). The merged images show that the Tms recognized by γ9d colocalize with a γ-actin within the myofiber and at the fiber periphery (C), whereas the CG3 Tms are not localized with γ-actin (F). In addition, signal for a γ-actin did not coincide with α-actinin (I, enlarged inset) indicating that γ-actin microfilaments are not closely associated with the myofibrils. The most intense γ-actin staining was at the myofiber periphery (B, E, H, and K), but the staining was mostly distinct from the sarcolemmal staining of dystrophin (L, inset). Bars, 20 μm.

Mentions: We next stained transverse sections of soleus muscle with the γ-actin antibody and the NS Tm antibodies to determine whether a γ-actin is part of the novel NS Tm filament structure in muscle (Fig. 6). From the merged images it is evident that there is almost complete colocalization of γ9d and γ-actin both within the myofiber and at the fiber periphery (Fig. 6 C). In contrast, the staining of CG3 appeared to be separate from γ-actin (Fig. 6 F, inset). This suggests that in skeletal muscle Tm5NM1 (detected by γ9d) is part of a γ-actin filament network, whereas the novel CG3 Tm (Tm5NM-34kd) associates with a different actin filament system. γ-Actin staining was not coincident with α-actinin (Fig. 6 I) and was concentrated in the subsarcolemmal space separate from dystrophin (Fig. 6 L). This pattern of staining is similar to γ9d and is consistent with a γ-actin–Tm5NM1 filament system located between the myofibrils and in the subsarcolemmal space.


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)

In transverse section, the γ9d Tms localize with a γ-actin, whereas the CG3 Tms do not. Shown are confocal images of transverse sections (7 μm) through soleus muscles stained with γ9d (A) or CG3 (D) and costained with a γ-actin antibody (B and E). The merged images show that the Tms recognized by γ9d colocalize with a γ-actin within the myofiber and at the fiber periphery (C), whereas the CG3 Tms are not localized with γ-actin (F). In addition, signal for a γ-actin did not coincide with α-actinin (I, enlarged inset) indicating that γ-actin microfilaments are not closely associated with the myofibrils. The most intense γ-actin staining was at the myofiber periphery (B, E, H, and K), but the staining was mostly distinct from the sarcolemmal staining of dystrophin (L, inset). Bars, 20 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2172434&req=5

fig6: In transverse section, the γ9d Tms localize with a γ-actin, whereas the CG3 Tms do not. Shown are confocal images of transverse sections (7 μm) through soleus muscles stained with γ9d (A) or CG3 (D) and costained with a γ-actin antibody (B and E). The merged images show that the Tms recognized by γ9d colocalize with a γ-actin within the myofiber and at the fiber periphery (C), whereas the CG3 Tms are not localized with γ-actin (F). In addition, signal for a γ-actin did not coincide with α-actinin (I, enlarged inset) indicating that γ-actin microfilaments are not closely associated with the myofibrils. The most intense γ-actin staining was at the myofiber periphery (B, E, H, and K), but the staining was mostly distinct from the sarcolemmal staining of dystrophin (L, inset). Bars, 20 μm.
Mentions: We next stained transverse sections of soleus muscle with the γ-actin antibody and the NS Tm antibodies to determine whether a γ-actin is part of the novel NS Tm filament structure in muscle (Fig. 6). From the merged images it is evident that there is almost complete colocalization of γ9d and γ-actin both within the myofiber and at the fiber periphery (Fig. 6 C). In contrast, the staining of CG3 appeared to be separate from γ-actin (Fig. 6 F, inset). This suggests that in skeletal muscle Tm5NM1 (detected by γ9d) is part of a γ-actin filament network, whereas the novel CG3 Tm (Tm5NM-34kd) associates with a different actin filament system. γ-Actin staining was not coincident with α-actinin (Fig. 6 I) and was concentrated in the subsarcolemmal space separate from dystrophin (Fig. 6 L). This pattern of staining is similar to γ9d and is consistent with a γ-actin–Tm5NM1 filament system located between the myofibrils and in the subsarcolemmal space.

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