title: Expression of tropomyosin-κ induces dilated cardiomyopathy and depresses cardiac myofilament tension by mechanisms involving cross-bridge dependent activation and altered tropomyosin phosphorylation.
abstract: Tropomyosin-kappa (TPM1-κ) is a newly discovered tropomyosin (TM) isoform that is exclusively expressed in the human heart and generated by an alternative splicing of the α-TM gene. We reported that TPM1-κ expression was increased in the hearts of patients with chronic dilated cardiomyopathy (DCM). To increase our understanding of the significance of this shift in isoform population, we generated transgenic (TG) mice expressing TPM1-κ in the cardiac compartment where TPM1-κ replaces 90% of the native TM. We previously showed that there was a significant inhibition of the ability of strongly bound cross-bridges to induce activation of TG myofilaments (Rajan et al., Circulation 121:410-418, 2010). Here, we compared the force-Ca(2+) relations in detergent extracted (skinned) fiber bundles isolated from non-transgenic (NTG) and TG-TPM1-κ hearts at two sarcomere lengths (SLs). Our data demonstrated a significant decrease in the Ca(2+) sensitivity of the myofilaments from TG-TPM1-κ hearts with no change in the maximum developed tension, length-dependent activation, and the ratio of ATPase rate to tension. There was also no difference in the affinity and cooperativity of Ca(2+)-binding to troponin in thin filaments reconstituted with either TPM1-κ or α-TM. We also compared protein phosphorylation in NTG and TG-TPM1-κ myofilaments. There was a decrease in the total phosphorylation of TPM1-κ compared to α-TM, but no significant change in other major sarcomeric proteins. Our results identify a novel mode of myofilament desensitization to Ca(2+) associated with a DCM linked switch in TM isoform population.
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave. (M/C 901), Chicago, IL 60612-7342, USA.
authors.forename: Chehade N
authors.initials: CN
authors.lastname: Karam
authors.forename: Chad M
authors.initials: CM
authors.lastname: Warren
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.forename: Pieter P
authors.initials: PP
authors.lastname: de Tombe
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D010766:Phosphorylation; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism*
chemical_list: D014335:Tropomyosin; D002118:Calcium