Understanding the Mechanisms of SPEG in Diabetes Induced HFpEF

Objective: Comparing the role of striated preferentially expressed gene (SPEG) in type II diabetes induced heart failure with preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF). Hypothesis: We hypothesized that SPEG behaves in a compensatory manner in diabetes induced HFpEF as compared to HFrEF which slowly impairs calcium handling, contributing to slow progression of diastolic dysfunction and disease development. Background: In the USA alone 38.2 million people were diagnosed with diabetes in CDC’s most recent statistical analysis from 2021. Type II diabetes is also a major risk factor for cardiovascular diseases, with HFpEF being the most common type of heart failure in type II diabetic patients yet it remains heavily understudied. We aimed to understand the metabolic-cardiac interplay at a molecular level by comparing the role of SPEG in HFpEF murine models with studies conducted in HFrEF models. Methods: We developed a type II diabetes murine model using a high-fat diet (HFD) combined with L-NAME to induce HFpEF. After 5 weeks on diet, we did echocardiography, glucose tolerance test (GTT), and extracted mice hearts to perform quantitative polymerase chain reaction (qPCR) to assess SPEG at the mRNA level. Data: Our GTT at five weeks confirmed the induction of type II diabetes with an overall glucose level of (403.00 ± 19.99 milligram(mg)/deciliter) in HFD + L-NAME mice. Our qPCR showed elevated mRNA levels of SPEG (2.47 ± 1.30) normalized to ribosomal protein L7 (RPL7) in HFpEF induced mice as compared to control mice (1.00 ± 0.66). This is a deviation from the lowered SPEG mRNA levels observed in human patients with low left ventricular ejection fraction (22.50 ± 1.71 %) a characteristic of HFrEF (Quick et al. 2017). We also observed increased heart weight to tibial length (HW/TL) ratio in diabetic mice with HFpEF (10.39 ± 2.24 mg/millimeter(mm)) as compared to control mice (6.60 ± 0.85 mg/mm), as well as increased heart weight to body weight (HW/BW) ratios in diabetic mice with HFpEF (0.00638 ± 0.00106 gram) as compared to control mice (0.00550 ± 0.00050 gram) which are essential parameters of cardiac hypertrophy. Summary: The results showed that the SPEG mRNA levels in diabetes induced HFpEF mice upregulated at the 5-week mark despite the mice showing typical signs of cardiac hypertrophy contrary to what has been previously reported in HFrEF patients (Quick et al. 2017). This might be due to the physiological system undergoing a compensatory phase in HFpEF models and upregulating SPEG to mediate the stress effects before the SPEG potentially downregulates. Conclusion: HFpEF is a slow progressing disease as compared to HFrEF and differences in SPEG levels at the disease onset might be a contributing factor in the diverse severity levels of both diseases. For future directions, we will be conducting comparative studies to assess mice models that have been on HFD + L-NAME for longer than 10-15 weeks and evaluate the SPEG levels to see how they compare with HFrEF mice models to find therapeutic approaches that are streamlined uniquely to the progression of each disease. Citations: Quick, Ann P., et al. “SPEG (Striated Muscle Preferentially Expressed Protein Kinase) Is Essential for Cardiac Function by Regulating Junctional Membrane Complex Activity.” Circulation Research, vol. 120, no. 1, 2017, pp. 110–119. doi:10.1161/CIRCRESAHA.116.309977. Funding: Texas A&M Startup Funds by AgriLife for Aguilar Lab This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.