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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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Inappropriate expression of an NS Tm (Tm3) results in muscular dystrophy phenotype and ragged-red fibers. The Tm3 mice have a number of features characteristic of muscular dystrophy in quadriceps (A–C) and soleus muscles (D–F). Features characteristic of muscular dystrophy shown in H&E stained transverse sections (A–F) include: areas of regenerating fibers with centralized nuclei (B, C, and F, black arrows), myofiber size variability (B, C, and F), and regions of fiber degeneration (F, white arrow), macrophage infiltration (B and F, black double arrows) and fibrosis (F, white arrowhead). Soleus muscle from Tm3 mice also has the characteristic accumulation of sarcolemmal mitochondria that is associated with ragged red fibers. Mitochondrial accumulations (black arrowheads) were observed in Gomori-Trichrome (G) and H&E stained (E) sections in of soleus of line 3/66 mice. The large increase in number and size of mitochondria beneath the sarcolemma is clearly evident in electron micrographs from Tm3 mice (J) compared with WT mice (I). Asterisks in I and J mark the subsarcolemmal mitochondria. Bars, A–H, 40 μm. When suspended by the tail the Tm3 mice (line 3/66; L), unlike the WT mice (K), are unable to extend their hindlimbs away from the body. This phenomenon has been observed in a mouse model of muscular dystrophy (Bittner et al., 1999).
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fig9: Inappropriate expression of an NS Tm (Tm3) results in muscular dystrophy phenotype and ragged-red fibers. The Tm3 mice have a number of features characteristic of muscular dystrophy in quadriceps (A–C) and soleus muscles (D–F). Features characteristic of muscular dystrophy shown in H&E stained transverse sections (A–F) include: areas of regenerating fibers with centralized nuclei (B, C, and F, black arrows), myofiber size variability (B, C, and F), and regions of fiber degeneration (F, white arrow), macrophage infiltration (B and F, black double arrows) and fibrosis (F, white arrowhead). Soleus muscle from Tm3 mice also has the characteristic accumulation of sarcolemmal mitochondria that is associated with ragged red fibers. Mitochondrial accumulations (black arrowheads) were observed in Gomori-Trichrome (G) and H&E stained (E) sections in of soleus of line 3/66 mice. The large increase in number and size of mitochondria beneath the sarcolemma is clearly evident in electron micrographs from Tm3 mice (J) compared with WT mice (I). Asterisks in I and J mark the subsarcolemmal mitochondria. Bars, A–H, 40 μm. When suspended by the tail the Tm3 mice (line 3/66; L), unlike the WT mice (K), are unable to extend their hindlimbs away from the body. This phenomenon has been observed in a mouse model of muscular dystrophy (Bittner et al., 1999).

Mentions: We next examined the effect of expression of Tm3 on muscle pathology (Fig. 9). Muscles from Tm3 mice showed classical signs of muscular dystrophy as visualized by hematoxylin and eosin (H&E) staining of cross sections. This includes large areas of myofiber degeneration, macrophage infiltration and fibrosis and regions of small regenerating fibers with centralized nuclei (Fig. 9, B, C, and F). Dystrophic features were observed in both transgenic lines (3/66 and 3/70) and in a number of different muscles: the quadriceps (Fig. 9, B and C), soleus (Fig. 9 F), gastrocnemius, and back muscles (results not depicted for latter two sets of muscles).


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)

Inappropriate expression of an NS Tm (Tm3) results in muscular dystrophy phenotype and ragged-red fibers. The Tm3 mice have a number of features characteristic of muscular dystrophy in quadriceps (A–C) and soleus muscles (D–F). Features characteristic of muscular dystrophy shown in H&E stained transverse sections (A–F) include: areas of regenerating fibers with centralized nuclei (B, C, and F, black arrows), myofiber size variability (B, C, and F), and regions of fiber degeneration (F, white arrow), macrophage infiltration (B and F, black double arrows) and fibrosis (F, white arrowhead). Soleus muscle from Tm3 mice also has the characteristic accumulation of sarcolemmal mitochondria that is associated with ragged red fibers. Mitochondrial accumulations (black arrowheads) were observed in Gomori-Trichrome (G) and H&E stained (E) sections in of soleus of line 3/66 mice. The large increase in number and size of mitochondria beneath the sarcolemma is clearly evident in electron micrographs from Tm3 mice (J) compared with WT mice (I). Asterisks in I and J mark the subsarcolemmal mitochondria. Bars, A–H, 40 μm. When suspended by the tail the Tm3 mice (line 3/66; L), unlike the WT mice (K), are unable to extend their hindlimbs away from the body. This phenomenon has been observed in a mouse model of muscular dystrophy (Bittner et al., 1999).
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Related In: Results  -  Collection

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fig9: Inappropriate expression of an NS Tm (Tm3) results in muscular dystrophy phenotype and ragged-red fibers. The Tm3 mice have a number of features characteristic of muscular dystrophy in quadriceps (A–C) and soleus muscles (D–F). Features characteristic of muscular dystrophy shown in H&E stained transverse sections (A–F) include: areas of regenerating fibers with centralized nuclei (B, C, and F, black arrows), myofiber size variability (B, C, and F), and regions of fiber degeneration (F, white arrow), macrophage infiltration (B and F, black double arrows) and fibrosis (F, white arrowhead). Soleus muscle from Tm3 mice also has the characteristic accumulation of sarcolemmal mitochondria that is associated with ragged red fibers. Mitochondrial accumulations (black arrowheads) were observed in Gomori-Trichrome (G) and H&E stained (E) sections in of soleus of line 3/66 mice. The large increase in number and size of mitochondria beneath the sarcolemma is clearly evident in electron micrographs from Tm3 mice (J) compared with WT mice (I). Asterisks in I and J mark the subsarcolemmal mitochondria. Bars, A–H, 40 μm. When suspended by the tail the Tm3 mice (line 3/66; L), unlike the WT mice (K), are unable to extend their hindlimbs away from the body. This phenomenon has been observed in a mouse model of muscular dystrophy (Bittner et al., 1999).
Mentions: We next examined the effect of expression of Tm3 on muscle pathology (Fig. 9). Muscles from Tm3 mice showed classical signs of muscular dystrophy as visualized by hematoxylin and eosin (H&E) staining of cross sections. This includes large areas of myofiber degeneration, macrophage infiltration and fibrosis and regions of small regenerating fibers with centralized nuclei (Fig. 9, B, C, and F). Dystrophic features were observed in both transgenic lines (3/66 and 3/70) and in a number of different muscles: the quadriceps (Fig. 9, B and C), soleus (Fig. 9 F), gastrocnemius, and back muscles (results not depicted for latter two sets of muscles).

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