As its long-term goal, the Sadayappan Lab aims to delineate the role of myosin binding protein- C (MyBP- C) structure, regulation and function in striated muscles of both cardiac and skeletal tissues. MyBP-C is localized in the inner two-thirds of the A band, the so-called C zone. Importantly, in humans, mutations in the cardiac MyBP-C gene are associated with familial hypertrophic and dilated cardiomyopathy, accounting for over 40% of all mutations linked to cardiomyopathies. To prevent the development of either hypertrophic or dilated cardiomyopathy at the early stage, the causal defect in the gene encoding cMyBP-C must be elucidated. MyBP- C binds to titin, myosin, actin and tropomyosin filaments as a transverse filament protein connecting both thick and thin filaments in the sarcomere. MyBP-C has three isoforms encoded by three distinct genes: fast-skeletal, slow-skeletal and cardiac. The cardiac isoform differs from the skeletal isoform by having an extra Ig domain at the N-terminus (C0), three phosphorylation sites within the MyBP-C motif region and a module (C5) that has an inserted loop of 28 residues. However, the differential roles of these isoforms in striated muscles remain unclear. Importantly, studies have shown that the cardiac isoform undergoes several different post- translational modifications, such as phosphorylation, glutathionylation, acetylation, carboxylation, O-GlcNAcylation and Citrullination, indicating that cMyBP-C is a regulatory protein and a central target of sarcomeric signaling. Some of these modifications alter MyBP-C proteolysis during muscle injury. Exactly how these modifications alter sarcomere regulation, structure and function is still unclear. Therefore, Sadayappan is committed to exploring the regulation of MyBP-C in various preclinical and clinical conditions using in vitro, ex vivo and in vivo approaches.

  • » cMyBP-C regulation, structure and function : cMyBP-C is a140-kDa sarcomeric thick filament protein that is necessary to regulate sarcomere structure and function in the heart. Based on our most recent studies, it can be considered a trans-filament protein because of its ability to connect both thick (myosin S2) and thin filament (actin and -tropomyosin) proteins via its amino terminal region. The long-term objective of the lab is to understand the functional consequences of cMyBP-C on heart function. In particular, the ongoing studies are focused on determining the specific role(s) of the amino terminal-region of cMyBP-C in regulating myosin (S2 region), sarcomere structure and function at the cardiac sarcomeric and whole-heart levels, leading to the development of potential cardioprotective therapeutic approaches to improve cardiac function in heart failure.
  • » Improving heart failure with preserved ejection fraction : Heart failure is the number one killer worldwide with heart failure with preserved ejection fraction (HFpEF, heart failure symptoms with normal systolic, but depressed diastolic function) comprising ~50% of heart failure cases. Type 2 diabetes (T2D) is a major risk factor for abnormal diastolic function, an early predictor of HFpEF. The presence of both HFpEF and T2D is associated with strikingly increased morbidity and mortality. However, currently, no effective pathophysiology-specific treatment is available for patients with HFpEF apart from general supportive care. Given the epidemic of obesity, HFpEF will become an even more prevalent highly morbid disease unless an effective treatment is developed. Therefore, ongoing studies in the lab are aimed at defining the molecular mechanism(s) underlying the development of HFpEF, particularly in the setting of T2D.
  • » Molecular mechanism of hypertrophic cardiomyopathy : Over the past two decades, the Sadayappan Lab has made significant contributions towards understanding the development of HCM. This has comprised a variety of clinical and animal strategies, including poison polypeptide, haploinsufficiency, inflammation and oxidative stress. The long-term objective is to understand the pathogenesis of MYBPC3 genetic variants known to cause HCM in South Asian descendants. In particular, the present studies are focused on determining the molecular mechanism underlying the pathogenicity of MYBPC3 and MYH7 mutations using human iPSC-CMs, Organoids and mouse models, leading to the discovery of cardioprotective agents to prevent or ameliorate HCM and heart failure.
  • » Autoimmune mechanisms in post-myocardial injury : Chronic inflammation following myocardial infarction (MI) has a detrimental effect on reperfusion, myocardial remodeling and cardiac function, and it is increasingly associated with high morbidity and mortality with a 50% 5-year mortality rate. The activation of macrophages and T-cells correlates with several clinical conditions and disease prognosis of heart failure and sudden cardiac death. Inflammation is often triggered by cardiac muscle proteins released into the blood following injury. cMyBP-C is very sensitive to degradation post-ischemia-reperfusion injury. Both full- length cMyBP-C and its N’-terminal fragments are released into the blood, predominantly a key 40 kDa N’-terminal protein that serves as an early biomarker of myocardial infarction. cMyBP-C proteolysis induces autoantibodies in mice and patients with cardiomyopathy and myocardial infarction. However, the immunological, inflammatory and pathophysiological roles of cMyBP-C remain unknown.
  • » Slow and fast skeletal MyBP-C structure and function : The myosin binding protein-C (MyBP-C) family is a group of sarcomeric proteins important for striated muscle structure and function. Comprising approximately 2% of the myofilament mass, MyBP-C has important roles in both contraction and relaxation. Three paralogs of MyBP-C are encoded by separate genes with distinct expression profiles in striated muscle. In mammals, cMyBP- C is limited to the heart (MYBPC3), and it is the most extensively studied owing to its involvement in cardiomyopathies. However, the roles of two skeletal paralogs, slow (MYBPC1) and fast (MYBPC2), in muscle biology remain poorly characterized. Nonetheless, both have been recently implicated in the development of skeletal myopathies. This calls for a better understanding of their function in the pathophysiology of distal arthrogryposis. Our ongoing studies are focused on determining the regulation, structure and function of slow and fast MyBP-C in skeletal muscle by using in vitro and in vivo studies using various knockout and knock-in mouse models.
  • » Myoarchitectural basis of heart failure : We propose to study the molecular and mechanical underpinnings of the ischemic myocardium in terms of its multi-scale organizational features, an attribute termed cardiac myoarchitecture. Cardiac myoarchitecture, as depicted by generalized Q-space MRI (GQI), is defined as the orientation and distribution of cardiac myocytes in the ventricular wall and forms a meso- scale template for contractility. Pathological cardiac myoarchitecture, on the other hand, manifests as architectural disarray, and contributes to impaired contractility of the ventricular wall. We have used GQI to depict myocardial injury due to ischemia-reperfusion in terms of its architectural features, and have demonstrated that constitutive phosphorylation of MYBPC3 reduces its ischemia-driven proteolytic degradation and promotes myoarchitectural protection. The goal of the ongoing project is to assess the mechanism by which ischemia- induced MYBPC3 de-phosphorylation causes proteolytic degradation, which, in turn, promotes sarcomere instability, architectural disarray, and mechanical impairment, and how, conversely, phosphorylation of MYBPC3 promotes architectural protection.
  • » cMyBP-C as a biomarker of early myocardial infarction : Over the last several years, the Sadayappan Lab has been engaged in exploring cMyBP-C as a potential biomarker of early myocardial infarction. Elevated level of serum cMyBP-C is an indicator of early myocardial infarction, but its value as a predictor of future cardiovascular disease is unknown. Acute coronary syndrome (ACS) describes a variety of conditions usually caused by rupture or erosion of atherosclerotic plaque within a coronary artery. One in three cases of myocardial infarction (MI) is not recognized by either patient or physician because chest pain is absent or atypical. Similarly, 70% of ACS cases ultimately do not have acute cardiac-related issues. Nonetheless, early identification of MI is important because it carries a high (50%) mortality rate. This rate can be substantially reduced by early aggressive treatment. NSTEMI is best diagnosed by measuring the release of plasma proteins from necrotic cardiomyocytes, but these proteins can only be detected from 4-12 hrs after MI. Therefore, there is a need to identify early biomarkers that can reliably rule out ACS, yet detect myocardial ischemia in the absence of irreversible myocyte injury. According to American Heart Association guidelines, a cardiomyocyte-specific biomarker should be measured for MI. cTnI and cTnT have significant drawbacks because they are released slowly and are elevated in a variety of pathophysiological conditions, not just MI. Although ACS is a medical emergency, many patients who present with ACS and are hospitalized for biomarker testing are unnecessarily exposed to anti-platelet and anti-thrombotic treatments. In addition,60-70% of cases are discharged with false-positive results. Although the latest generation of highly sensitive or ultrasensitive cTnl assays can detect MI at an earlier stage compared to the conventional assay, these new assays are so sensitive that they also detect low concentrations of cTnl that are not necessarily indicative of MI. In fact, their positive predictive value can be as low as 50% in selected patient populations. We recently showed that cMyBP-C might be a cardiomyocyte-specific plasma biomarker for the early detection of MI because it has significantly higher titers than cTnI. The objectives of the ongoing study are focused on determining and developing cMyBP-C as a biomarker of early-onset MI.

For queries and opportunities, Please Contact :

Sakthivel Sadayappan, PhD, MBA
Professor of Internal Medicine
Associate Chairman for Basic Research
Department of Internal Medicine
Director of Heart Branch of the Heart, Lung and Vascular Institute
Division of Cardiovascular Health and Disease
University of Cincinnati, College of Medicine
Cardiovascular Center, Rm 4935
231 Albert Sabin Way
Cincinnati, OH 45267-0542, USA
Phone : +1 513-558-7498
Email : sadayasl@ucmail.uc.edu

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