Myofilament calcium sensitivity and cardiac disease: insights from troponin I isoforms and mutants.
The heightened Ca2+ sensitivity of force found with hypertrophic cardiomyopathy (HCM)-associated mutant cardiac troponin I (cTnIR145G; R146G in rodents) has been postulated to be an underlying cause of hypertrophic growth and premature sudden death in humans and in animal models of the disease. Expression of slow skeletal TnI (ssTnI), a TnI isoform naturally expressed in developing heart, also increases myofilament Ca2+ sensitivity, yet its expression in transgenic mouse hearts is not associated with overt cardiac disease. Gene transfer of TnI isoforms or mutants into adult cardiac myocytes is used here to ascertain if expression levels or functional differences between HCM TnI and ssTnI could help explain these divergent organ-level effects. Results showed significantly reduced myofilament incorporation of cTnIR146G compared with ssTnI or wild-type cTnI. Despite differences in myofilament incorporation, ssTnI and cTnIR146G expression each resulted in enhanced myofilament tension in response to submaximal Ca2+ under physiological ionic conditions. Myofilament expression of an analogous HCM mutation in ssTnI (ssTnIR115G) did not further increase myofilament Ca2+ sensitivity of tension compared with ssTnI. In contrast, there was a divergent response under acidic pH conditions, a condition associated with the myocardial ischemia that often accompanies hypertrophic cardiomyopathy. The acidic pH-induced decrease in myofilament Ca2+ sensitivity was significantly greater in myocytes expressing cTnIR146G and ssTnIR115G compared with ssTnI. These results suggest that differences in pH sensitivities between wild-type ssTnI and mutant TnI proteins may be one factor in helping explain the divergent organ and organismal outcomes in TnI HCM- and ssTnI-expressing mice.
Westfall
Margaret V
MV
Department of Surgery, School of Medicine, University of Michigan, Ann Arbor, Mich 48109-0686, USA.
Borton
Andrea R
AR
Albayya
Faris P
FP
Metzger
Joseph M
JM
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000494:pharmacology*; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006331:Heart Diseases / Q000378:metabolism / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D019210:Troponin I / Q000235:genetics / Q000378:metabolism*; D016276:Ventricular Function
D020033:Protein Isoforms; D019210:Troponin I; D002118:Calcium