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Role of Epigenetic Mechanisms in the Pathogenesis of Idiopathic Inflammatory Myopathies Open Access

The idiopathic inflammatory myopathies (IIM) (polymyositis [PM], dermatomyositis [DM], and inclusion body myositis [IBM]) are a heterogeneous group of disorders characterized by chronic muscle weakness, muscle fatigue, and mononuclear cell infiltration into skeletal muscle. The etiology of these disorders is currently unknown; however, disease onset in a subset of individuals has been associated with environmental agents, suggesting that specific exposure, in the context of certain genetic backgrounds, can initiate muscle inflammation. Common environmental agents implicated in myositis include infectious organisms, such as viruses, parasites, and bacteria, and non-infectious agents, such as drugs and UV radiation exposure [1, 2]. Attempts to identify viruses in the tissues of IIM patients have failed, bringing into question the viral etiology of these diseases and ruling out continual viral infection as a cause of the ongoing muscle inflammation in these patients [3]. However, these studies did not exclude the possibility that viruses may alter the epigenome in affected cells and initiate pathogenic processes prior to their elimination by the host’s immune response, thus explaining the absence of viral genomes and presence of type I interferon signature gene expression in the myositis muscle tissue [4-7]. Here we propose that it is unlikely that a unique environmental agent initiates the myositis disease phenotype, but instead it is highly likely that a diverse group of common environmental agents cause tissue specific epigenetic and gene expression alterations leading to perturbation in cell homeostasis, survival, and death, which explain the manifestation of a disease phenotype in persons with a susceptible genetic background. In order to explore this hypothesis, we postulate that epigenetic changes that occur at the onset of disease likely contribute to disease processes. We investigated the epigenetic mechanisms that control the downstream pathways in the muscle at disease onset, as well as epigenetic mechanisms that respond to therapeutic interventions (i.e. exercise and Rituximab) after disease onset. We found that epigenetic mechanisms at disease onset affect mitochondrial function, which contributes to disease by perpetuating muscle damage. Additionally, we found that interventions that boost mitochondrial function, such as exercise, alleviate symptoms by altering the epigenome in order to promote mitochondrial health, decrease viral signature genes, and improve muscle damage. We further found that Rituximab alters estrogen receptor (ESR-1) mediated signaling – a known pathway that promotes mitochondrial health – through epigenetic regulation. This work supports the hypothesis that myositis pathology is in part regulated at the epigenetic level. Further, these epigenetic alterations contribute to mitochondrial dysfunction, a hypothesized non-immune mechanisms of disease. Therefore, treatments that target the mitochondria, as well as disease-causing epigenetic mechanisms, in muscle may provide benefit to patients with substantial muscle damage.

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