Functional consequence of mutation in rat cardiac troponin T is affected differently by myosin heavy chain isoforms.
Cardiac troponin T (cTnT) is an essential component of the thin filament regulatory unit (RU) that regulates Ca2+ activation of tension in the heart muscle. Because there is coupling between the RU and myosin crossbridges, the functional outcome of cardiomyopathy-related mutations in cTnT may be modified by the type of myosin heavy chain (MHC) isoform. Ca2+ activation of tension and ATPase activity were measured in muscle fibres from normal rat hearts containing alpha-MHC isoform and propylthiouracil (PTU)-treated rat hearts containing beta-MHC isoform. Muscle fibres from normal and PTU-treated rat hearts were reconstituted with two different mutations in rat cTnT; the deletion of Glu162 (cTnT(E162DEL)) and the deletion of Lys211 (cTnT(K211DEL)). Alpha-MHC and beta-MHC isoforms had contrasting impact on tension-dependent ATP consumption (tension cost) in cTnT(E162DEL) and cTnT(K211DEL) reconstituted muscle fibres. Significant increases in tension cost in alpha-MHC-containing muscle fibres corresponded to 17% (P < 0.01) and 23% (P < 0.001) when reconstituted with cTnT(E162DEL) and cTnT(K211DEL), respectively. In contrast, tension cost decreased when these two cTnT mutants were reconstituted in muscle fibres containing beta-MHC; by approximately 24% (P < 0.05) when reconstituted with cTnT(E162DEL) and by approximately 17% (P = 0.09) when reconstituted with cTnT(K211DEL). Such differences in tension cost were substantiated by the mechano-dynamic analysis of cTnT mutant reconstituted muscle fibres from normal and PTU-treated rat hearts. Our observation demonstrates that qualitative changes in MHC isoform alters the nature of cardiac myofilament dysfunction induced by mutations in cTnT.
Tschirgi
Matthew L
ML
Department of Veterinary Comparative Anatomy Pharmacology and Physiology (VCAPP), Washington State University, WA 99164, USA.
Rajapakse
Indika
I
Chandra
Murali
M
D019943:Amino Acid Substitution; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000503:physiopathology*; D003198:Computer Simulation; D008955:Models, Cardiovascular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D020107:Troponin T / Q000235:genetics / Q000378:metabolism*
D020033:Protein Isoforms; D020107:Troponin T; D018995:Myosin Heavy Chains