37PMolecular differences between regenerating and inflamed myofibers in Inclusion body myositis

The skeletal muscle tissue is heterogeneous in cell composition, predominantly composed of myofibers that determine muscle physiology. In aging and muscle diseases myofiber undergo alterations such as atrophy, regeneration, and inflammation. In Inclusion Body Myositis (IBM), an adult-onset condition, muscle weakness is accompanied by immune cells infiltration and the presence of regenerating myofibers. The molecular mechanisms underlying myofiber alterations to regenerating or inflamed states is poorly understood. We applied Laser-Capture Microdissection (LCM) mass spectrometry on immunostained cryosections of the vastus lateralis to identify protein networks and molecular signatures associated with IBM histopathology. Comparing IBM to control muscles, we observed downregulation of muscle and mitochondrial protein networks and upregulation of immune-related proteins, consistent with muscle weakness and inflammation in IBM. Analysis of myofiber specific signatures revealed that inflamed myofibers had limited similarities with centrally nucleated myofibers and embryonic myosin heavy chain (eMyHC) positive fibers, which were more similar to each other. Unique to each myofiber region we found proteins related to protein folding enriched in centrally nucleated fibers, while protein associated with granulation and the proteasome were enriched in both eMyHC positive myofiber and centrally nucleated myofibers. Additionally, aggregation-prone proteins were significantly enriched in IBM and inflamed myofibers. Overall, this study identifies myofiber-specific molecular signatures in IBM and highlights aggregation-prone proteins providing new insights into the molecular mechanisms underlying myofiber alteration.