04PNovel mouse model for inclusion body myositis: transgenic upregulation of lymphotoxin together with impaired autophagy induces inflammation and protein accumulation in skeletal muscle

Inclusion body myositis (IBM) is a progressive muscle disorder characterized by inflammation and degeneration with altered proteostasis. To better understand the interrelationship between these two features, we aimed at establishing a novel preclinical IBM model. First, we used quantitative PCR to determine expression of pro-inflammatory chemo- and cytokines including lymphotoxin (LT)-signaling pathway components in human skeletal muscle tissue diagnosed with myositis. Based on these results we generated a mouse model that we analyzed at the histological, ultrastructural, transcriptional, biochemical, and behavioural level. Lastly, we subjected this model to anti-inflammatory treatments. After confirming and extending previous data on activation of lymphotoxin (LT)-signaling in human myositis, we generated a transgenic mouse line co-expressing LTalpha and -beta in skeletal muscle fibers. Transgenic mice displayed chronic myositis accompanied by dysregulated proteostasis, including an altered autophagolysosomal pathway. Related genes were temporarily up- and later downregulated, possibly in a compensatory manner. Therefore, we genetically impaired autophagy in skeletal muscle cells. Autophagy impairment alone induced a pro-inflammatory transcriptional state, but no obvious cellular inflammation. However, the combination of LT-driven myositis with autophagy impairment induced the full spectrum of characteristic molecular and pathological features of IBM in skeletal muscle, including protein aggregates with typical ultrastructural morphology and mild mitochondrial pathology. Our attempts to treat the pathology by subjecting these mice to corticosteroids or anti-Thy1.2 antibodies mirrored recent treatment failures in humans, i.e., none of these treatments resulted in significant clinical improvement of motor performance or the transcriptional profile of muscle pathology. In summary, these data provide evidence that inflammation and autophagy disruption play a synergistic role in the development of IBM-like muscular pathology. Furthermore, once established, IBM-like pathology in these mice, as in human IBM patients cannot be reverted or prevented from progression by conventional means of immunosuppression. We expect that this novel mouse model will help to identify future treatment modalities for IBM.