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Research Overview

A major focus of Guo lab (Muscle Biology Laboratory, MBL) is to understand the molecular basis and cell signaling pathways underlying cardiomyopathies, heart failure and skeletal muscle myopathy. Another major focus of MBL is to study the life course impact of fetal programming on cardiac and skeletal muscle development and function. Understanding of these mechanisms may help to develop novel therapeutic strategies for treatment of cardiac and skeletal muscle diseases, as well as muscle growth and regeneration to improve meat quality and quantity in livestock. My three ongoing projects are to 1) decipher the molecular mechanisms of RNA binding motif 20 (RBM20)-mediated myocardial stiffness in heart failure with preserved ejection fraction (HFpEF); 2) understand the molecular mechanisms regulating skeletal muscle regeneration and myopathy; and 3) determine the impact of maternal obesity on striated muscle function of offspring during life course.



Ongoing Projects


Project 1

Decipher the molecular mechanisms of RNA binding motif 20 (RBM20)-mediated myocardial stiffness in heart failure with preserved ejection fraction (HFpEF)

Heart failure (HF) is a major public health issue and remains the leading cause of morbidity, mortality, and hospitalization among adults and the elderly. In the US, the total medical cost for patients with HF is expected to rise to $50 billion by 2030. HF is characterized and clinically defined by the inability of the heart to supply sufficient normal blood perfusion to organs and tissues. About half of HF patients show near normal contractile function and often hypertrophied heart (HFpEF) but with abnormal diastolic function. However, currently, no effective therapeutic options are available for HFpEF. Hence, novel molecular mechanisms need to be explored, and novel therapeutic targets for HFpEF prevention and therapy are urgently required.

TTN, a major human disease gene, encodes the giant sarcomeric protein titin that is a potential therapeutic target for the treatment of HFpEF because it is recognized as a major determinant of myocardial stiffness. The elastic properties of titin may support elastic recoil in early diastole and are a major determinant of the end-diastolic stiffness that determines filling. Titin has two isoforms and the varying ratios of these two isoforms alter myocardial stiffness (Fig. 1). Therefore, adjusting titin isoform ratios can be a potential therapeutic strategy for the treatment of HFpEF by reducing the myocardial stiffness. RNA binding motif 20 (RBM20) is the main regulator of the titin isoform switching leading to the production of two major classes of isoforms: N2B and N2BA (Fig. 1). Rbm20 knockout (KO) rats produce only the N2BA isoform and show a reduction in diastolic stiffness. Similarly, increased titin size and compliance through changing RBM20 expression in genetic murine model improves diastolic dysfunction. Since hormones such as insulin and thyroid hormones can regulate titin isoform ratios through RBM20, and RBM20 is a serine-arginine (SR) protein which can be phosphorylated, our study in this project will focus on the detailed mechanisms of how RBM20 regulates titin splicing through signaling pathways and posttranslational modifications (Fig. 2).
Figure 1. Schematic diagram for the impacty of the ratios of titin sizes on passive tension of cardiomyocytes at the same sarcomere length.
Figure 2. Schematic diagram for the RMB20-mediated titin alternative splicing through the signaling pathways and posttranslational modifications.

Project 2

Understand the molecular mechanisms of RBM20 in regulating skeletal muscle growth, regeneration and myopathy

Muscle growth is the net effect when protein synthesis exceeds protein degradation. Small changes in either the protein synthesis rate or the rate of protein turnover (degradation rate) have profound effects on net protein deposition and rate of growth. In order to increase the efficiency of lean muscle accretion, a better understanding of those basic biological mechanisms in skeletal muscle tissue is necessary. In addition, muscle regeneration normally occurs after impairment in skeletal muscle function including injury, disease and aging. Intensive research has been done to address the regenerative mechanisms which are involved in acute muscle injuries and chronic muscle diseases. However, the exact molecular mechanisms and effects on muscle remodeling remain unknown. Our lab found that RBM20 could be a major gene that can impair the muscle regeneration after injury (Fig. 3), which is our focus to study the role of RBM20 in muscle growth, regeneration and myopathies. 

Figure 3. Role of RMB20 in muscle regeneration after injury.

Project 3

Determine the impact of maternal obesity on striated muscle function of offspring during life course in sheep model

Obesity is an exponentially increasing public health epidemic and economic burden worldwide. Currently, 18– 35% of pregnant women in the United States are obese. Epidemiologic studies suggest that maternal obesity (MO) during pregnancy exhibits intergenerational effects by programming offspring to increased risk of obesity, skeletal muscle development and cardiometabolic problems, including insulin resistance and heart disease. Both maternal under- and overnutrition play important roles in programming fetal striated muscle development and function. Sheep share many similarities with human pregnancy (i.e., singleton gestation being the most common litter size, which is important in terms of the nutritional burden placed on the mother; comparable maternal size and adiposity; maternal: fetal weight ratio; length of gestation, important in the duration of nutritional challenges; birth weight; similar organogenesis for major body systems; equivalent rates of prenatal protein accretion and fat deposition; and relative maturity at birth). Therefore, studies in precocial species are necessary to enable translation to programming in human development. This project is using sheep as model to study the effect of MO programming on the fetal heart (Fig. 4) and skeletal muscle development.

Figure 4. Schematic diagram depicting the signaling pathways linking MO to fetal heart contractile dysfunction.

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