Sorting of a nonmuscle tropomyosin to a novel cytoskeletal compartment in skeletal muscle results in muscular dystrophy.
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.
Kee
Anthony J
AJ
Muscle Development Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, New South Wales 2145, Australia.
Schevzov
Galina
G
Nair-Shalliker
Visalini
V
Robinson
C Stephen
CS
Vrhovski
Bernadette
B
Ghoddusi
Majid
M
Qiu
Min Ru
MR
Lin
Jim J-C
JJ
Weinberger
Ron
R
Gunning
Peter W
PW
Hardeman
Edna C
EC
D000818:Animals; D002451:Cell Compartmentation / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009137:Muscular Dystrophy, Animal / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D021381:Protein Transport / Q000235:genetics; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
D020033:Protein Isoforms; C411923:Tpm3 protein, mouse; D014335:Tropomyosin