METABOLIC AND STRUCTURAL MUSCULAR CHANGES DRIVEN BY CHRONIC DISEASE-LIKE IFN-G EXPOSURE

Abstract

Abstract Cardiovascular myopathies and fatigue have been associated with chronic inflammatory responses and activated cell-mediated immunity. We report aberrant cardiovascular activity in the form of reduced ejection fraction in vivo in male mice with persistent low-level expression of IFN-g (ARE mice). ARE mice have a replacement with random nucleotides in the 3 prime UTR of the IFN-g gene that serves to remove a regulatory element (AU Rich) that is integral at controlling the stability of IFN-g mRNA. ARE mice had increased cellular and mineral, infiltrates into heart tissue and mitochondria linked metabolic changes that were concomitantly observed following a stress-exacerbated decrease in heart function, with or without exposure to IFN-a. Our data also demonstrates an increase in glucose expenditure and increased general fatigue of ARE mice as well as structural and ultrastructural changes in the heart in male mice. We also observe a decrease in the transcripts and a reversible decrease in function of aerobic respiratory components in the muscle of male mice exposed to IFN-g. Notably, we observe a decrease in X chromosome linked pyruvate dehydrogenase, a key component in pyruvate facilitated entry to the TCA cycle, and other downstream mitochondrial genes. Furthermore, the in vivo data revealed an increase in factors associated with fatigue, such as lactic acid production and changes in expression of genes associated with an increase inanaerobic respiration in cardiac musculature. These results indicate that the chronic expression of IFN-g results in a model for male biased heart failure understress in an autoimmune environment, like the idiopathic cardiomyopathy found in male Systemic Lupus Erythematosus patients.