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Published 30 August 2004. doi:10.1083/jcb.200406181
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 5, 685-696
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Article

 Sorting of a nonmuscle tropomyosin to a novel cytoskeletal compartment in skeletal muscle results in muscular dystrophy

Anthony J. Kee1, Galina Schevzov2,5, Visalini Nair-Shalliker1, C. Stephen Robinson1, Bernadette Vrhovski2, Majid Ghoddusi1, Min Ru Qiu3, Jim J.-C. Lin4, Ron Weinberger2,5, Peter W. Gunning2, and Edna C. Hardeman1

1 Muscle Development Unit, Children's Medical Research Institute, Wentworthville, New South Wales 2145, Australia
2 Oncology Research Unit, The Children's Hospital at Westmead, Parramatta, New South Wales 2145, Australia
3 John Douglass Centre for Structural Pathology, The Children's Hospital at Westmead, Parramatta, New South Wales 2145, Australia
4 Department of Biological Sciences, The University of Iowa, Iowa City, IA 52242
5 Discipline of Pediatrics and Child Health, University of Sydney, Sydney, New South Wales 4000, Australia

Address correspondence to Edna C. Hardeman, Muscle Development Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, New South Wales 2145, Australia. Tel.: 61-2-9687-2800. Fax: 61-2-9687-2120. email: ehardeman{at}cmri.usyd.edu.au

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.

Key Words: tropomyosin; muscles; muscular dystrophies; transgenic mice; sarcomeres

The Muscle Development Unit and Oncology Research Unit contributed equally to this work.

Abbreviations used in this paper: EDL, extensor digitorum longus; EOM, extraocular muscles; H&E, hematoxylin and eosin; MHC, myosin heavy chain; NS, nonsarcomeric; Tm, tropomyosin.


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