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Myosin binding protein C: implications for signal-transduction.

Knöll R - J. Muscle Res. Cell. Motil. (2011)

Bottom Line: While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood.However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play.Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure.

View Article: PubMed Central - PubMed

Affiliation: Imperial College, National Heart and Lung Institute, British Heart Foundation-Centre for Research Excellence, Myocardial Genetics, London, UK. r.knoell@imperial.ac.uk

ABSTRACT
Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure.

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Summary of possible pathologic events caused by a primary increase in calcium sensitivity, which has been shown to be present in various Mybpc3 transgenic animal models as well as in patients affected by mutations in the MYBPC3 gene. CamKII calmodulin dependent kinase II, PKC protein kinase C
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Fig4: Summary of possible pathologic events caused by a primary increase in calcium sensitivity, which has been shown to be present in various Mybpc3 transgenic animal models as well as in patients affected by mutations in the MYBPC3 gene. CamKII calmodulin dependent kinase II, PKC protein kinase C

Mentions: It might well be that MYBPC3 mutations are primarily linked to an increase in calcium sensitivity, but it is difficult to link this event directly to the secondary effects such as myocardial hypertrophy including myofibrillar disarray, fatal arrhythmias and sudden cardiac death (Fig. 4). One hypothesis proposes energy deficiency due to reduced thermal efficiency in HCM or another hypothesis states that troponin C functions as an intracellular calcium buffer or calcium store (Bers 2008). An increase in calcium sensitivity could affect calcium transients, which indeed have been found to be increased in Myh6 Arg403Gln knock in animals (Gao et al. 1999). An increase in calcium transients may also have effects on calcium dependent enzymes such as calcineurin, calmodulin dependent kinase, and protein kinase C all of which have been shown to be important for the initiation of myocardial hypertrophy (Kubis et al. 2003).Fig. 4


Myosin binding protein C: implications for signal-transduction.

Knöll R - J. Muscle Res. Cell. Motil. (2011)

Summary of possible pathologic events caused by a primary increase in calcium sensitivity, which has been shown to be present in various Mybpc3 transgenic animal models as well as in patients affected by mutations in the MYBPC3 gene. CamKII calmodulin dependent kinase II, PKC protein kinase C
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351598&req=5

Fig4: Summary of possible pathologic events caused by a primary increase in calcium sensitivity, which has been shown to be present in various Mybpc3 transgenic animal models as well as in patients affected by mutations in the MYBPC3 gene. CamKII calmodulin dependent kinase II, PKC protein kinase C
Mentions: It might well be that MYBPC3 mutations are primarily linked to an increase in calcium sensitivity, but it is difficult to link this event directly to the secondary effects such as myocardial hypertrophy including myofibrillar disarray, fatal arrhythmias and sudden cardiac death (Fig. 4). One hypothesis proposes energy deficiency due to reduced thermal efficiency in HCM or another hypothesis states that troponin C functions as an intracellular calcium buffer or calcium store (Bers 2008). An increase in calcium sensitivity could affect calcium transients, which indeed have been found to be increased in Myh6 Arg403Gln knock in animals (Gao et al. 1999). An increase in calcium transients may also have effects on calcium dependent enzymes such as calcineurin, calmodulin dependent kinase, and protein kinase C all of which have been shown to be important for the initiation of myocardial hypertrophy (Kubis et al. 2003).Fig. 4

Bottom Line: While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood.However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play.Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure.

View Article: PubMed Central - PubMed

Affiliation: Imperial College, National Heart and Lung Institute, British Heart Foundation-Centre for Research Excellence, Myocardial Genetics, London, UK. r.knoell@imperial.ac.uk

ABSTRACT
Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure.

Show MeSH
Related in: MedlinePlus