Abstract 14377: Alteration in Cardiac Function via Upregulation of Interferon Pathway in Skeletal Muscle

Introduction: Cardiac abnormalities are a major cause of death in patients with myositis. Chronic inflammation resulting from increased infiltration of inflammatory cells in skeletal muscle followed by muscle weakness and myofiber atrophy is a characteristic of myositis. Transcriptomics and myopathological studies show IFN-1 pathway play a major role in pathophysiology of myositis. However, we do not understand how does IFN-1 signaling from inflamed skeletal muscle regulates cardiac function. Interferon regulatory factor 3 (IRF3) is a key transcriptional regulator of IFN-1 signaling cascade. Here we generated a skeletal muscle-specific IRF3 transgenic mouse model that recapitulates muscle atrophy and cardiac dysfunction facilitated by tissue cross-talk via elevated IFN-1 levels. Hypothesis: Persistent inflamed microenvironment by IRF3 and IFN-1 levels in skeletal muscle impairs muscle fitness, alters metabolome as well as myokine signaling and generates cardiac stress followed by impaired cardiac metabolism. Methods: Skeletal muscle-specific transgenic mouse model with constitutive activation of IRF3 was exploited to mimic sustained IFN-1 signaling found in myositis in vivo. Effect on muscle inflammation and weakness was determined by gene expression analysis and forelimb grip strength. Effect on cardiac inflammation, mitochondrial function, and heart function was examined. Histological assessment was done to determine fiber cross-sectional area and fiber type in whole muscle and myocytes. Results: Our data show increased mRNA levels of IRF3 in muscle atrophy model. Characterization of skeletal muscle-specific IRF3 transgenic mice showed activation of genes regulating IFN-1 pathway ( Isg15 , Ifit1 , Rsad2 , and Mx2 , etc.) and macrophage infiltration ( CD14 , CD68 ) in skeletal as well as cardiac muscle. In vitro and in vivo histological analysis showed alteration in fiber type markers. The inflammatory milieu generated by IRF3 altered metabolome and myokine levels affecting transcriptional molecular circuits regulating tissue cross-talk and metabolic pathways in the heart. Conclusion: Our studies identified skeletal muscle-specific activation of IRF3 as a model to study IFN-1 induced damage to cardiac function in vivo.