Myosin-Binding Protein C Phosphorylation, Myofibril Structure, and Contractile Function During Low-Flow Ischemia

Decker, Robert S.; Decker, Marlene L.; Kulikovskaya, Irina; Nakamura, Sakie; Lee, Daniel; Harris, Kathleen R.; Klocke, Francis J.; Winegrad, Saul

doi:10.1161/01.cir.0000155609.95618.75

Cited by 78 publications

(96 citation statements)

References 27 publications

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“…Expression of cMyBP-C AllPϩ resulted in significant protection from I-R injury with relatively conserved cardiac function and less cellular damage. cMyBP-C AllPϩ was also highly resistant to the peptide cleavage associated with ischemia (17). Similar data have been obtained for PKA-mediated cardiac troponin I phosphorylation, which significantly reduced troponin I proteolysis (28).…”

Section: Discussionsupporting

confidence: 76%

“…We recently reported that total cMyBP-C phosphorylation, particularly the triphosphorylated species, was decreased in mice with I-R injury (14). This finding is consistent with data from Decker et al (17), who found that cMyBP-C is dephosphorylated and its degradation accelerated during low-flow ischemia. Thus, reduced phosphorylation of cMyBP-C is associated with contractile dysfunction.…”

supporting

confidence: 92%

“…The primary mechanisms responsible for decreased function after I-R is caused by acidosis and reduced Ca 2ϩ sensitivity of the contractile myofilaments. There is also a transient elevation of intracellular Ca 2ϩ that activates Ca 2ϩ -calmodulin-activated kinase and protease-like calpain I, leading to cleavage of cardiac troponin I, ␣-actinin, the myosin light chains (24), and cMyBP-C (17). cMyBP-C is dephosphorylated during low-flow ischemia (17) and in I-R-based heart failure models (14).…”

Section: Discussionmentioning

confidence: 99%

“…There is also a transient elevation of intracellular Ca 2ϩ that activates Ca 2ϩ -calmodulin-activated kinase and protease-like calpain I, leading to cleavage of cardiac troponin I, ␣-actinin, the myosin light chains (24), and cMyBP-C (17). cMyBP-C is dephosphorylated during low-flow ischemia (17) and in I-R-based heart failure models (14). Decreased phosphorylation would have the net effect of increasing thick filament packing density, possibly leading to reduced calcium-activated force generation (25).…”

Section: Discussionmentioning

confidence: 99%

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Cardiac myosin binding protein c phosphorylation is cardioprotective

Sadayappan

Osińska

Klevitsky

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

190

294

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Cardiac myosin binding protein C (cMyBP-C) has three phosphorylatable serines at its N terminus (Ser-273, Ser-282, and Ser-302), and the residues' phosphorylation states may alter thick filament structure and function. To examine the effects of cMyBP-C phosphorylation, we generated transgenic mice with cardiac-specific expression of a cMyBP-C in which the three phosphorylation sites were mutated to aspartic acid, mimicking constitutive phosphorylation (cMyBP-C AllP؉ ). The allele was bred into a cMyBP-C null background (cMyBP-C (t/t) ) to ensure the absence of endogenous dephosphorylated cMyBP-C. cMyBP-C AllP؉ was incorporated normally into the cardiac sarcomere and restored normal cardiac function in the null background. However, subtle changes in sarcomere ultrastructure, characterized by increased distances between the thick filaments, indicated that phosphomimetic cMyBP-C affects thick-thin filament relationships, and yeast two-hybrid data and pull-down studies both showed that charged residues in these positions effectively prevented interaction with the myosin heavy chain. Confirming the physiological relevance of these data, the cMyBP-C AllP؉:(t/t) hearts were resistant to ischemia-reperfusion injury. These data demonstrate that cMyBP-C phosphorylation functions in maintaining thick filament spacing and structure and can help protect the myocardium from ischemic injury.heart ͉ ischemia C ardiac myosin binding protein C (cMyBP-C) is localized to the sarcomere's thick filaments where it has structural and regulatory functions. MYBPC3 mutations account for 20-30% of all mutations linked to familial hypertrophic cardiomyopathy (1). cMyBP-C belongs to the intracellular Ig superfamily and is composed of Ig and fibronectin type-3 repeating domains (Fig. 1A). It is present not only in cardiac muscle, but also in skeletal muscle before the skeletal muscle-type isoforms are expressed, suggesting that the cardiac isoform is functional in early myofibrillogenesis and regenerating muscle (2, 3). cMyBP-C may modulate myosin assembly (4) and stabilize thick filaments (5). It binds titin via domains C8-C10 (6) and actin in the Pro-Alarich sequences between the C0 and C1 domains (7), which appear to be important for the precise arrangement of the actin-myosin filaments. Compared with the two skeletal muscle isoforms, the cardiac isoform contains an extra Ig domain at the N terminus (C0), an insertion of 28 residues within the C5 domain, and three potential phosphorylation sites that are substrates for cAMP-dependent PKA, Ca 2ϩ -calmodulin-activated kinase, and PKC (8). This region is located between the C1 and C2 domains of the N terminus, which binds to the subfragment 2 (S2) segment of myosin close to the lever arm domain (9-11), and this interaction may be dynamically regulated by the differential phosphorylation of cMyBP-C (12). cMyBP-C is the only thick filament protein that is differentially phosphorylated at multiple sites by the enzymes PKA, PKC, and Ca 2ϩ -calmodulin-activated kinase (13). Reconstitution studie...

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Section: Discussionsupporting

confidence: 76%

supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Cardiac myosin binding protein c phosphorylation is cardioprotective

Sadayappan

Osińska

Klevitsky

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

190

294

View full text Add to dashboard Cite

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“…In 2000, TnI and TnT have been approved as the biomarkers for AMI diagnosis [42], and several kits have been commercially developed and used in clinical studies [43][44][45]. In addition to TnI and TnT, other myofilament proteins, including TnC [46], LC2 [46], aactinin [32] and MyBP-C [47], were also reported as useful markers in animal models of ischemia/reperfusion injury. Two mechanisms are believed to be responsible for most myofilament protein degradation.…”

Section: Degradationmentioning

confidence: 99%

Myofilament proteins: From cardiac disorders to proteomic changes

Yuan

Solaro

2008

Proteomics Clinical Apps

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Myofilament proteins of the cardiac sarcomere house the molecular machinery responsible for generating tension and pressure. Release of intracellular Ca 21 triggers myofilament tension generation and shortening, but the response to Ca 21 is modulated by changes in key regulatory proteins. We review how these proteomic changes are essential to adaptive physiological regulation of cardiac output and become maladaptive in cardiac disorders. We also review the essentials of proteomic techniques used to study myofilament protein changes, including degradation, isoform expression, phosphorylation and oxidation. Selected proteomic studies illustrate the applications of these approaches.

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Force relaxation and thin filament protein phosphorylation during acute myocardial ischemia

Han

Ogut

2010

Cytoskeleton

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Ischemia impairs myocardial function and may contribute to the progression of heart failure. In this study, rats subjected to acute ischemia demonstrated reduced Ca 2+ activated force as well as a decrease in myosin binding protein-C, titin and Ser23/24 phosphorylation of troponin I (TnI). All three proteins have been demonstrated to be downstream targets of β-adrenergic receptor activation (β-AR), leading to the hypothesis that decreased β-AR during ischemia leads to reduced protein phosphorylation and reduced rate constants of force relaxation. To test this hypothesis, force relaxation transients were recorded from permeabilized perfused and ischemic rat heart fibers following photolysis of the caged chelator diazo-2. Relaxation transients were best fit by double exponential functions whereby the majority (>70%) of the force decline was described by the fast rate constant, which was ~5 times faster than the slow rate constant. However, rate constants of relaxation between perfused and ischemic fibers were not different, despite significant decreases in sarcomeric protein phosphorylation in ischemic fibers. Treatment of perfused fibers with a cAMP analog increased Ser23/24 phosphorylation of TnI, yet the rate constants of relaxation remained unchanged. Interestingly, similar treatment of ischemic fibers did not impact TnI phosphorylation or force relaxation transients. Therefore, acute ischemia does not influence the rate constants of relaxation of permeabilized fibers. These results also suggest that the physiological level of sarcomeric protein phosphorylation is unlikely to be the primary driver of relaxation kinetics in permeabilized cardiac muscle fibers.

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Myosin-Binding Protein C Phosphorylation, Myofibril Structure, and Contractile Function During Low-Flow Ischemia

Cited by 78 publications

References 27 publications

Cardiac myosin binding protein c phosphorylation is cardioprotective

Cardiac myosin binding protein c phosphorylation is cardioprotective

Myofilament proteins: From cardiac disorders to proteomic changes

Force relaxation and thin filament protein phosphorylation during acute myocardial ischemia

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