Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)
Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in t...
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doaj-a15b31b712f7450db776b864cdd7c9072020-11-24T22:35:51ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2017-06-01810.3389/fphys.2017.00348262349Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)Andrew E. Messer0Jasmine Chan1Alex Daley2O'Neal Copeland3Steven B. Marston4David J. Connolly5Myocardial Function, NHLI, Imperial College LondonLondon, United KingdomThe Royal Veterinary CollegeHatfield, United KingdomThe Royal Veterinary CollegeHatfield, United KingdomMyocardial Function, NHLI, Imperial College LondonLondon, United KingdomMyocardial Function, NHLI, Imperial College LondonLondon, United KingdomThe Royal Veterinary CollegeHatfield, United KingdomHypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20–44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non-HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 ± 0.13 fold) Ca2+-sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 μM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model.http://journal.frontiersin.org/article/10.3389/fphys.2017.00348/fullFelix catusRagdoll cathypertrophic cardiomyopathycardiac muscleCa2+ regulationtroponin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrew E. Messer Jasmine Chan Alex Daley O'Neal Copeland Steven B. Marston David J. Connolly |
spellingShingle |
Andrew E. Messer Jasmine Chan Alex Daley O'Neal Copeland Steven B. Marston David J. Connolly Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus) Frontiers in Physiology Felix catus Ragdoll cat hypertrophic cardiomyopathy cardiac muscle Ca2+ regulation troponin |
author_facet |
Andrew E. Messer Jasmine Chan Alex Daley O'Neal Copeland Steven B. Marston David J. Connolly |
author_sort |
Andrew E. Messer |
title |
Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus) |
title_short |
Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus) |
title_full |
Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus) |
title_fullStr |
Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus) |
title_full_unstemmed |
Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus) |
title_sort |
investigations into the sarcomeric protein and ca2+-regulation abnormalities underlying hypertrophic cardiomyopathy in cats (felix catus) |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2017-06-01 |
description |
Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20–44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non-HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 ± 0.13 fold) Ca2+-sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 μM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model. |
topic |
Felix catus Ragdoll cat hypertrophic cardiomyopathy cardiac muscle Ca2+ regulation troponin |
url |
http://journal.frontiersin.org/article/10.3389/fphys.2017.00348/full |
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