The <i>NORAD</i> -Pumilio regulatory axis in the evolution of inclusion body myositis

Sporadic inclusion body myopathy (sIBM) is the most common progressive degenerative skeletal muscle disease of older people with poorly understood pathogenesis. We assessed the involvement and impact of the noncoding RNA activated by DNA damage (NORAD) and its binding partner Pumilio (PUM) proteins on the evolution of the disease process in muscle biopsies from sIBM patients with mild or severe histopathologic changes. A disease severity-dependent increase in NORAD and PUM2 expression was present along with subsarcolemmal formations of NORAD-PUM (NP) bodies in the sIBM muscles. Similarly, Norad, Pum1, and Pum2 expression levels were upregulated as disease severity increased with age in VCP-A232E mice, a model for hereditary IBM. Crossbreeding VCP-A232E mice with Norad-/- mice leading to generation of VCP mutants with either single copy or the absence of Norad showed that Norad suppresses disease progression in the VCP-A232E model in a dose-dependent manner. Norad expression in the muscle from Pum2 overexpressing mice revealed significantly increased Norad transcripts in response to high Pum2 expression and the presence of NP bodies coalescing around muscle nuclei. Collectively, these findings provide strong evidence that elevated NORAD expression is a protective, compensatory response to disease-related induction of PUM2 activity in muscle.