Abstract Body: Background: Obesity is a major risk factor for heart disease. Mitochondrial ribosomal protein S5 (MRPS5) is a key component of the 28S small subunit of the mammalian mitochondrial ribosome. We previously demonstrated that reducing mitochondrial protein translation can trigger beneficial mitonuclear communication through a mitochondrial stress response; this enhanced cardiac regeneration after myocardial infarction. However, the role of Mrps5 reduction in cardiomyocytes under metabolic stress remains unknown.
Methods: We used a tamoxifen-inducible, cardiomyocyte-specific Mrps5 mouse model to examine the impact of Mrps5 reduction on cardiac function under metabolic stress. Eight-week-old male Mrps5^fl/+;Myh6-MCM and Mrps5^fl/+ mice were injected with tamoxifen to induce cardiomyocyte-specific Mrps5 reduction. Mice were subsequently fed either a control diet (10% kcal fat) or a high-fat, high-sucrose (HFHS) diet (60% kcal fat and 17.5% corn syrup in the drinking water) for 10 weeks.
Results: In agreement with our previous report, Mrps5 reduction in cardiomyocytes induced cardiac hypertrophy (increased HW/TL ratio and cardiomyocyte area) without impairing systolic function. The HFHS diet induced obesity-related metabolic disorders in both genotypes, with characteristic increases in body weight and adiposity, and glucose intolerance. In Mrps5^fl/+ mice, the HFHS diet caused cardiac hypertrophy (increased HW/TL ratio and cardiomyocyte area), reduced ejection fraction and fractional shortening, and decreased running distance and running time in a treadmill exercise–tolerance test, compared with Mrps5^fl/+ mice fed control diet. In contrast, these HFHS diet-induced alterations were not observed in Mrps5^fl/+;Myh6-MCM mice. Furthermore, qPCR analysis revealed that Mrps5^fl/+;Myh6-MCM mice exhibited an increase in expression of mitochondrial biogenesis–related genes (Ppargc1a and Ppara) in the heart in response to HFHS diet compared with Mrps5^fl/+ mice. Additionally, transmission electron microscope examination revealed that HFHS diet induced mitochondrial morphological alterations in the heart of Mrps5^fl/+ mice; however, these alterations were not observed in the heart of Mrps5^fl/+;Myh6-MCM mice upon HFHS diet.
Conclusion: Our preliminary data suggest that reducing cardiomyocyte-specific mitochondrial protein translation protects against obesity-induced exercise intolerance, cardiac hypertrophy, and reduced systolic function.