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Vol. 20, Issue 1, 400-409, January 1, 2009

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Cytoskeletal Tropomyosin Tm5NM1 Is Required for Normal Excitation–Contraction Coupling in Skeletal Muscle

Nicole Vlahovich^*,,,, Anthony J. Kee^*,||,, Chris Van der Poel^¶, Emma Kettle^*, Delia Hernandez-Deviez^#, Christine Lucas^*,@, Gordon S. Lynch^¶, Robert G. Parton^#, Peter W. Gunning^||,@,**, and Edna C. Hardeman^*,

*Muscle Development Unit, Children's Medical Research Institute, Westmead, NSW, Australia; University of Western Sydney, Parramatta, NSW, Australia; ^||Faculty of Medicine, University of Sydney, Sydney, NSW, Australia; ^¶Department of Physiology, University of Melbourne, Parkville, VIC, Australia; ^#Institute for Molecular Biosciences, University of Queensland and Centre for Microscopy and Microanalysis, Brisbane, QLD, Australia; ^@Oncology Research Unit, The Children's Hospital at Westmead, Westmead, NSW, Australia; **Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia; and Department of Anatomy, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

Submitted June 18, 2008; Revised October 17, 2008; Accepted October 31, 2008
Monitoring Editor: Thomas D. Pollard

The functional diversity of the actin microfilaments relies in part on the actin binding protein tropomyosin (Tm). The muscle-specific Tms regulate actin-myosin interactions and hence contraction. However, there is less known about the roles of the numerous cytoskeletal isoforms. We have shown previously that a cytoskeletal Tm, Tm5NM1, defines a Z-line adjacent cytoskeleton in skeletal muscle. Recently, we identified a second cytoskeletal Tm in this region, Tm4. Here we show that Tm4 and Tm5NM1 define separate actin filaments; the former associated with the terminal sarcoplasmic reticulum (SR) and other tubulovesicular structures. In skeletal muscles of Tm5NM1 knockout (KO) mice, Tm4 localization was unchanged, demonstrating the specificity of the membrane association. Tm5NM1 KO muscles exhibit potentiation of T-system depolarization and decreased force rundown with repeated T-tubule depolarizations consistent with altered T-tubule function. These results indicate that a Tm5NM1-defined actin cytoskeleton is required for the normal excitation–contraction coupling in skeletal muscle.

These authors contributed equally to this work.

Present address: The Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037.

Address correspondence to: Edna C. Hardeman (e.hardeman{at}unsw.edu.au).

Abbreviations used: DHPR, dihydropyridine receptor; DICR, depolarization-induced contractile response; EDL, extensor digitorum longus; EM, electron microscopy; FDB, flexor digitorum brevis; KO, knockout; MyHC, myosin heavy chain; SR, sarcoplasmic reticulum; Tm, tropomyosin; WT, wild type.