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

Ectopically expressed Tm3 accumulates adjacent to the Z-line and at the M-line. Shown are immunofluorescent confocal images of longitudinal and transverse sections of soleus muscle from adult Tm3 transgenic (line 3/66) and wild-type (WT) mice. WT soleus muscle contains two main Tm isoforms (Tm1 and Tm6; Fig. 7 A) recognized by the α9d antibody. Longitudinal and transverse sections (7 μm) of WT muscle indicate that these isoforms are present in structures outside of the myofiber and at the myofiber periphery (D and J, respectively). Tm3 (also detected by the α9d antibody; Fig. 1 A), is absent from WT muscle (Fig. 7 A), but in the Tm3 mice the ectopic protein is located at the Z-line adjacent region (A–C, 0.5–1.0 μm longitudinal sections; Z-line marked by arrows) and at the M-line (A and C, arrowheads). Tm3 localized mainly to the sarcomeric compartment (G and K) and was colocalized with the γ-actin antibody in longitudinal and cross sections (I and N, respectively). Bars: (A–C) 2.5 μm; (D–I) 40 μm; and (J–N) 20 μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172434&req=5

fig8: Ectopically expressed Tm3 accumulates adjacent to the Z-line and at the M-line. Shown are immunofluorescent confocal images of longitudinal and transverse sections of soleus muscle from adult Tm3 transgenic (line 3/66) and wild-type (WT) mice. WT soleus muscle contains two main Tm isoforms (Tm1 and Tm6; Fig. 7 A) recognized by the α9d antibody. Longitudinal and transverse sections (7 μm) of WT muscle indicate that these isoforms are present in structures outside of the myofiber and at the myofiber periphery (D and J, respectively). Tm3 (also detected by the α9d antibody; Fig. 1 A), is absent from WT muscle (Fig. 7 A), but in the Tm3 mice the ectopic protein is located at the Z-line adjacent region (A–C, 0.5–1.0 μm longitudinal sections; Z-line marked by arrows) and at the M-line (A and C, arrowheads). Tm3 localized mainly to the sarcomeric compartment (G and K) and was colocalized with the γ-actin antibody in longitudinal and cross sections (I and N, respectively). Bars: (A–C) 2.5 μm; (D–I) 40 μm; and (J–N) 20 μm.

Mentions: The ectopic Tm3 protein localized to the same Z-line adjacent region as the endogenous γ-TM gene isoforms (Tm5NM1 and Tm5NM-34kd; Fig. 8). Very strong staining either side of the Z-line can be seen in soleus longitudinal sections with the α9d antibody (Fig. 8, A and C). Ectopic Tm3 was mainly restricted to the cytoplasmic region of the myofiber (Fig. 8, G, K, and L). This staining is specific for ectopic Tm3 as although this antibody detects a number of different endogenous isoforms in the soleus muscle (Fig. 7 A) none of these are present in the cytoplasmic sarcomeric regions of the muscle (Fig. 8, D and J). In longitudinal and cross sections, ectopic Tm3 colocalized with the γ-actin antibody (Fig. 8, I and N, respectively). This is consistent with an association of Tm3 with a Z-line adjacent γ-actin cytoskeleton.


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)

Ectopically expressed Tm3 accumulates adjacent to the Z-line and at the M-line. Shown are immunofluorescent confocal images of longitudinal and transverse sections of soleus muscle from adult Tm3 transgenic (line 3/66) and wild-type (WT) mice. WT soleus muscle contains two main Tm isoforms (Tm1 and Tm6; Fig. 7 A) recognized by the α9d antibody. Longitudinal and transverse sections (7 μm) of WT muscle indicate that these isoforms are present in structures outside of the myofiber and at the myofiber periphery (D and J, respectively). Tm3 (also detected by the α9d antibody; Fig. 1 A), is absent from WT muscle (Fig. 7 A), but in the Tm3 mice the ectopic protein is located at the Z-line adjacent region (A–C, 0.5–1.0 μm longitudinal sections; Z-line marked by arrows) and at the M-line (A and C, arrowheads). Tm3 localized mainly to the sarcomeric compartment (G and K) and was colocalized with the γ-actin antibody in longitudinal and cross sections (I and N, respectively). Bars: (A–C) 2.5 μm; (D–I) 40 μm; and (J–N) 20 μm.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Ectopically expressed Tm3 accumulates adjacent to the Z-line and at the M-line. Shown are immunofluorescent confocal images of longitudinal and transverse sections of soleus muscle from adult Tm3 transgenic (line 3/66) and wild-type (WT) mice. WT soleus muscle contains two main Tm isoforms (Tm1 and Tm6; Fig. 7 A) recognized by the α9d antibody. Longitudinal and transverse sections (7 μm) of WT muscle indicate that these isoforms are present in structures outside of the myofiber and at the myofiber periphery (D and J, respectively). Tm3 (also detected by the α9d antibody; Fig. 1 A), is absent from WT muscle (Fig. 7 A), but in the Tm3 mice the ectopic protein is located at the Z-line adjacent region (A–C, 0.5–1.0 μm longitudinal sections; Z-line marked by arrows) and at the M-line (A and C, arrowheads). Tm3 localized mainly to the sarcomeric compartment (G and K) and was colocalized with the γ-actin antibody in longitudinal and cross sections (I and N, respectively). Bars: (A–C) 2.5 μm; (D–I) 40 μm; and (J–N) 20 μm.
Mentions: The ectopic Tm3 protein localized to the same Z-line adjacent region as the endogenous γ-TM gene isoforms (Tm5NM1 and Tm5NM-34kd; Fig. 8). Very strong staining either side of the Z-line can be seen in soleus longitudinal sections with the α9d antibody (Fig. 8, A and C). Ectopic Tm3 was mainly restricted to the cytoplasmic region of the myofiber (Fig. 8, G, K, and L). This staining is specific for ectopic Tm3 as although this antibody detects a number of different endogenous isoforms in the soleus muscle (Fig. 7 A) none of these are present in the cytoplasmic sarcomeric regions of the muscle (Fig. 8, D and J). In longitudinal and cross sections, ectopic Tm3 colocalized with the γ-actin antibody (Fig. 8, I and N, respectively). This is consistent with an association of Tm3 with a Z-line adjacent γ-actin cytoskeleton.

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