Abstract
Adult cardiac muscle normally expresses a single cardiac troponin T (cTnT). As a potential pathogenic mechanism for turkey dilated cardiomyopathy, the splice-out of a normally constitutive exon generates an additional low molecular weight cTnT with altered conformation and function. We further found that aberrant splicing of cTnT also occurs in several mammals correlating to dilated cardiomyopathy. Skipping of the same exon as that in the turkey was found in the canine cTnT. Splice-out of the adjacent exon 6 occurred in the guinea pig cTnT. Retention of the embryonic exon 5 was found in the cTnT of cat, dog, and guinea pig. These aberrant splicing variants significantly altered the structure of cTnT to sustain functional effects as that in the myopathic turkey cTnT. The genomic sequence of canine cTnT gene shows no specific alterations. However, the alternative splicing patterns of canine cTnT are different in developing cardiac and skeletal muscles, suggesting abnormality of trans-regulatory factors. Transgenic expression of the aberrant cTnT variants resulted in contractile changes in mouse cardiomyocytes. The findings support the hypothesis that thin filament heterogeneity due to the co-expression of alternatively spliced cTnT variants may desynchronize myocardial contraction and contribute to the pathogenesis and pathophysiology of cardiomyopathy and heart failure.
Highlights
Troponin T (TnT)1 is the anchoring subunit of the troponin complex in the thin filament regulatory system of vertebrate striated muscle [1]
In contrast to the fact that most adult avian and mammalian hearts express only a single cardiac troponin T (cTnT) isoform, we have found the expression of an additional cTnT splicing variant resulting from the exclusion of 12 amino acids encoded by the exon 8 in the heart of the dilated cardiomyopathy (DCM) turkey [13]
The adult mammalian heart normally expresses a single cTnT isoform or in a few species such as bovine and mouse, two very similar cTnT isoforms resulting from the inclusion or exclusion of the 4 –5 amino acids encoded by exon 4 (Fig. 1)
Summary
Troponin T (TnT) is the anchoring subunit of the troponin complex in the thin filament regulatory system of vertebrate striated muscle [1]. In contrast to the fact that most adult avian and mammalian hearts express only a single cTnT isoform, we have found the expression of an additional cTnT splicing variant resulting from the exclusion of 12 amino acids encoded by the exon 8 in the heart of the dilated cardiomyopathy (DCM) turkey [13]. This abnormal splicing pathway resulted in a low molecular weight cTnT exhibiting altered molecular conformation and binding affinity for troponin I (TnI) and tropomyosin (Tm). The findings support the hypothesis that thin filament heterogeneity due to the coexpression of alternatively spliced cTnT variants may desynchronize myocardial contraction and contribute to the pathogenesis and pathophysiology of cardiomyopathy and heart failure
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