Physiological significance of troponin T binding domains in striated muscle tropomyosin.
Striated muscle tropomyosin (TM) plays an essential role in sarcomeric contraction and relaxation through its regulated movement on the thin filament. Previous work in our laboratory established that alpha- and beta-TM isoforms elicit physiological differences in sarcomeric performance. To address the significance of isoform-specific troponin T binding regions in TM, in this present work we replaced alpha-TM amino acids 175-190 and 258-284 with the beta-TM regions and expressed this chimeric protein in the hearts of transgenic mice. Hearts that express this chimeric protein exhibit significant decreases in rates of contraction and relaxation when assessed by ex vivo work-performing cardiac analyses. There are increases in time to peak pressure and in half-time to relaxation. These hearts respond appropriately to beta-adrenergic stimulation but do not attain control rates of contraction or relaxation. With increased expression of the transgene, 70% of the mice die by 5 mo of age without exhibiting gross pathological changes in the heart. Myofilaments from these mice have no differences in Ca(2+) sensitivity of percent maximum force, but there is a decrease in maximum tension development. Our data are the first to demonstrate that the troponin T binding regions of specific TM isoforms can alter sarcomeric performance without changing the Ca(2+) sensitivity of the myofilaments.
Jagatheesan
Ganapathy
G
Dept. of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA.
Rajan
Sudarsan
S
Petrashevskaya
Natalia
N
Schwartz
Arnold
A
Boivin
Greg
G
Arteaga
Grace
G
de Tombe
Pieter P
PP
Solaro
R John
RJ
Wieczorek
David F
DF
D008841:Actin Cytoskeleton / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002678:Chimera; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000737:chemistry / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis; D020107:Troponin T / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D012333:RNA, Messenger; D020107:Troponin T; D007545:Isoproterenol; D002118:Calcium