Methyl donor deficiency induces cardiomyopathy through altered methylation/acetylation of PGC-1α by PRMT1 and SIRT1.

Cardiomyopathies occur by mechanisms that involve inherited and acquired metabolic disorders. Both folate and vitamin B12 deficiencies are associated with left ventricular dysfunction, but mechanisms that underlie these associations are not known. However, folate and vitamin B12 are methyl donors needed for the synthesis of S-adenosylmethionine, the substrate required for the activation by methylation of regulators of energy metabolism. We investigated the consequences of a diet lacking methyl donors in the myocardium of weaning rats from dams subjected to deficiency during gestation and lactation. Positron emission tomography (PET), microscope and metabolic examinations evidenced a myocardium hypertrophy, with cardiomyocyte enlargement, disturbed mitochondrial alignment, lipid droplets, decreased respiratory activity of complexes I and II and decreased S-adenosylmethionine:S-adenosylhomocysteine ratio. The increased concentrations of triglycerides and acylcarnitines were consistent with a deficit in fatty acid oxidation. These changes were explained by imbalanced acetylation/methylation of PGC-1α, through decreased expression of SIRT1 and PRMT1 and decreased S-adenosylmethionine:S-adenosylhomocysteine ratio, and by decreased expression of PPARα and ERRα. The main changes of the myocardium proteomic study were observed for proteins regulated by PGC-1α, PPARs and ERRα. These proteins, namely trifunctional enzyme subunit α-complex, short chain acylCoA dehydrogenase, acylCoA thioesterase 2, fatty acid binding protein-3, NADH dehydrogenase (ubiquinone) flavoprotein 2, NADH dehydrogenase (ubiquinone) 1α-subunit 10 and Hspd1 protein, are involved in fatty acid oxidation and mitochondrial respiration. In conclusion, the methyl donor deficiency produces detrimental effects on fatty acid oxidation and energy metabolism of myocardium through imbalanced methylation/acetylation of PGC-1α and decreased expression of PPARα and ERRα. These data are of pathogenetic relevance to perinatal cardiomyopathies.

Long-term survival after a massive left ventricular infarction evidenced by FDG-PET and leaving intact only the septal wall.

There is evidence that survival remains possible for infarction greater than 50% of the left ventricle in human, as well as in the rat infarct model. To our knowledge, survival has not been documented for infarctions involving the anterior, inferior and lateral wall leaving intact only the septal wall. An adult rat underwent a ligation of the left anterior descending coronary artery. ECG-triggered (18)F-ffluorodeoxyglucose Positron Emission Tomography revealed that 72% of the left ventricle was necrotic and totally akinetic. Although the left ventricular ejection fraction was severely impaired (9%), this rat survived and was asymptomatic after 2 months. The exact reasons for this incredible survival are still unclear.

Evaluation of a rat knee mono-arthritis using microPET.

AIM: Assessing the activity of synovitis, which is characterized by an increase in cell metabolism, is important for the prediction of future articular destruction in clinical and preclinical studies. To evaluate the correlation between ¹8F-FDG accumulation and arthritis pathology during its establishment, we used microPET to evaluted ¹8F-FDG accumulation in vivo during rat Mycobacterium wall-induced knee arthritis. METHODS: ¹8F-FDG PET images of arthritic rats were acquired on days 1, 2, 3 and 7 after arthritis induction. The subjects (n=2/time) were subsequently subjected to macro-autoradiography, and ¹8F-FDG accumulation was compared with histological findings. RESULTS: ¹8F-FDG PET images depicted swollen joints, and ¹8F-FDG accumulation increased with the progression of arthritis. Histologically, increased ¹8F-FDG accumulation correlated with the pannus rather than the infiltration of inflammatory cells around the joints. CONCLUSION: ¹8F-FDG accumulation in arthritis reflects proliferating pannus and inflammatory activity enhanced by inflammatory cytokines. ¹8F-FDG microPET should be effective for quantifying the inflammatory activity of arthritis and/or its therapeutic response.