Limits...
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.

Show MeSH

Related in: MedlinePlus

Schematic representation of NS Tm localization in skeletal muscle. Depicted are myofibers in longitudinal (A) and transverse section (B) showing the location of the NS Tms and γ-actin in relation to the major structures in skeletal muscle. (A) In the longitudinal representation, two main membrane/cytoskeletal junctions are depicted: (1) integrin-based focal adhesions and (2) the dystrophin glycoprotein complex. Hypothesized tropomyosin-associated γ-actin networks that link the sarcomeric arrays to the costamere are shown as black lines. Other filaments linking the M-line and Z-line to the membrane are not depicted. The results of this study suggest that the NS tropomyosins recognized by the γ9d and CG3 antibodies (Tm5NM1 and Tm5NM-34kd, respectively) are located adjacent to the Z-line in the sarcomeric space. Data suggest that Tm5NM1 associates with a γ-actin whereas the actin (broken black line) interacting with Tm5NM-34kd was not defined. Note that although α-actinin (pink) is only shown cross-linking γ-actin filaments, its main location is in the Z-line linking sarcomeric actin thin filaments from adjacent sarcomeres. (B) In the transverse representation, Tm5NM1 (blue) and Tm5NM-34kd (green) are shown in the intermyofibrillar space, the former in association with a γ-actin and the later with an unknown actin filament system. Also shown is Tm5NM1/γ-actin filaments at the subsarcolemmal region, a space also occupied by mitochondria. The data suggests that the Tm5NM1 filaments are in all adult fibers, whereas the Tm5NM-34kd structure is restricted to specialized subset of fibers. The ectopic Tm3 localizes to the Z-line–associated γ-actin cytoskeleton and results in muscular dystrophy and ragged-red fibers.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172434&req=5

fig10: Schematic representation of NS Tm localization in skeletal muscle. Depicted are myofibers in longitudinal (A) and transverse section (B) showing the location of the NS Tms and γ-actin in relation to the major structures in skeletal muscle. (A) In the longitudinal representation, two main membrane/cytoskeletal junctions are depicted: (1) integrin-based focal adhesions and (2) the dystrophin glycoprotein complex. Hypothesized tropomyosin-associated γ-actin networks that link the sarcomeric arrays to the costamere are shown as black lines. Other filaments linking the M-line and Z-line to the membrane are not depicted. The results of this study suggest that the NS tropomyosins recognized by the γ9d and CG3 antibodies (Tm5NM1 and Tm5NM-34kd, respectively) are located adjacent to the Z-line in the sarcomeric space. Data suggest that Tm5NM1 associates with a γ-actin whereas the actin (broken black line) interacting with Tm5NM-34kd was not defined. Note that although α-actinin (pink) is only shown cross-linking γ-actin filaments, its main location is in the Z-line linking sarcomeric actin thin filaments from adjacent sarcomeres. (B) In the transverse representation, Tm5NM1 (blue) and Tm5NM-34kd (green) are shown in the intermyofibrillar space, the former in association with a γ-actin and the later with an unknown actin filament system. Also shown is Tm5NM1/γ-actin filaments at the subsarcolemmal region, a space also occupied by mitochondria. The data suggests that the Tm5NM1 filaments are in all adult fibers, whereas the Tm5NM-34kd structure is restricted to specialized subset of fibers. The ectopic Tm3 localizes to the Z-line–associated γ-actin cytoskeleton and results in muscular dystrophy and ragged-red fibers.

Mentions: Using antibodies to γ-TM gene products (γ9d and CG3) and an antibody to a γ-actin, a novel structural compartment in muscle has been identified. This compartment is present at a very restricted area adjacent to the Z-line. Analysis of muscle transverse sections suggests that within this compartment there are at least two separate structures located in the intermyofibrillar space. One, labeled by γ9d, containing Tm5NM1, appears to be associated with a γ-actin filament network, and the other, defined by CG3 (Tm5NM-34kd), appears to be part of a separate filament system. The localization of Tm5NM1 and Tm5NM-34kd in the intermyofibrillar space aligned adjacent to the Z-line suggests there are filament networks that laterally interconnects the Z-line adjacent region of individual myofibrils (Fig. 10 A). This system would be analogous to the desmin intermediate filament network that laterally interlinks the Z-disks of each myofibril (Capetanaki, 2002).


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)

Schematic representation of NS Tm localization in skeletal muscle. Depicted are myofibers in longitudinal (A) and transverse section (B) showing the location of the NS Tms and γ-actin in relation to the major structures in skeletal muscle. (A) In the longitudinal representation, two main membrane/cytoskeletal junctions are depicted: (1) integrin-based focal adhesions and (2) the dystrophin glycoprotein complex. Hypothesized tropomyosin-associated γ-actin networks that link the sarcomeric arrays to the costamere are shown as black lines. Other filaments linking the M-line and Z-line to the membrane are not depicted. The results of this study suggest that the NS tropomyosins recognized by the γ9d and CG3 antibodies (Tm5NM1 and Tm5NM-34kd, respectively) are located adjacent to the Z-line in the sarcomeric space. Data suggest that Tm5NM1 associates with a γ-actin whereas the actin (broken black line) interacting with Tm5NM-34kd was not defined. Note that although α-actinin (pink) is only shown cross-linking γ-actin filaments, its main location is in the Z-line linking sarcomeric actin thin filaments from adjacent sarcomeres. (B) In the transverse representation, Tm5NM1 (blue) and Tm5NM-34kd (green) are shown in the intermyofibrillar space, the former in association with a γ-actin and the later with an unknown actin filament system. Also shown is Tm5NM1/γ-actin filaments at the subsarcolemmal region, a space also occupied by mitochondria. The data suggests that the Tm5NM1 filaments are in all adult fibers, whereas the Tm5NM-34kd structure is restricted to specialized subset of fibers. The ectopic Tm3 localizes to the Z-line–associated γ-actin cytoskeleton and results in muscular dystrophy and ragged-red fibers.
© Copyright Policy
Related In: Results  -  Collection

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

fig10: Schematic representation of NS Tm localization in skeletal muscle. Depicted are myofibers in longitudinal (A) and transverse section (B) showing the location of the NS Tms and γ-actin in relation to the major structures in skeletal muscle. (A) In the longitudinal representation, two main membrane/cytoskeletal junctions are depicted: (1) integrin-based focal adhesions and (2) the dystrophin glycoprotein complex. Hypothesized tropomyosin-associated γ-actin networks that link the sarcomeric arrays to the costamere are shown as black lines. Other filaments linking the M-line and Z-line to the membrane are not depicted. The results of this study suggest that the NS tropomyosins recognized by the γ9d and CG3 antibodies (Tm5NM1 and Tm5NM-34kd, respectively) are located adjacent to the Z-line in the sarcomeric space. Data suggest that Tm5NM1 associates with a γ-actin whereas the actin (broken black line) interacting with Tm5NM-34kd was not defined. Note that although α-actinin (pink) is only shown cross-linking γ-actin filaments, its main location is in the Z-line linking sarcomeric actin thin filaments from adjacent sarcomeres. (B) In the transverse representation, Tm5NM1 (blue) and Tm5NM-34kd (green) are shown in the intermyofibrillar space, the former in association with a γ-actin and the later with an unknown actin filament system. Also shown is Tm5NM1/γ-actin filaments at the subsarcolemmal region, a space also occupied by mitochondria. The data suggests that the Tm5NM1 filaments are in all adult fibers, whereas the Tm5NM-34kd structure is restricted to specialized subset of fibers. The ectopic Tm3 localizes to the Z-line–associated γ-actin cytoskeleton and results in muscular dystrophy and ragged-red fibers.
Mentions: Using antibodies to γ-TM gene products (γ9d and CG3) and an antibody to a γ-actin, a novel structural compartment in muscle has been identified. This compartment is present at a very restricted area adjacent to the Z-line. Analysis of muscle transverse sections suggests that within this compartment there are at least two separate structures located in the intermyofibrillar space. One, labeled by γ9d, containing Tm5NM1, appears to be associated with a γ-actin filament network, and the other, defined by CG3 (Tm5NM-34kd), appears to be part of a separate filament system. The localization of Tm5NM1 and Tm5NM-34kd in the intermyofibrillar space aligned adjacent to the Z-line suggests there are filament networks that laterally interconnects the Z-line adjacent region of individual myofibrils (Fig. 10 A). This system would be analogous to the desmin intermediate filament network that laterally interlinks the Z-disks of each myofibril (Capetanaki, 2002).

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