12PBioengineered muscle-on-a-chip for the study of inclusion body myositis

Inclusion Body Myositis (IBM) is an inflammatory myopathy affecting 1-180 patients per million, mainly over 50 years old. It is characterized by muscle weakness of quadriceps and forearms. Diagnosis involves pathological analysis of muscle biopsies with degenerative (fiber size variation, vacuolization), immunological (MHC-I expression, CD8+ cell infiltrates), and mitochondrial (ragged red and COX-/SDH+ fibers) changes. There are no effective treatments, and current models for drug testing fail to reproduce pathological muscle structure and microenvironment. We aim to overcome this limitation using patient-derived 3D Muscle-on-a-Chip (MoC) platforms. We encapsulated an immortalized myoblast control line exposed to sera from 4 IBM and 4 healthy subjects for 48, 96, and 144 hours. We validated the model by checking skeletal muscle structure (sarcomeric alpha actinin staining) and function (Fluo-8 calcium flux). We performed Electric Pulse Stimulation to measure biophysical parameters and molecular phenotyping to characterize functional impairment. Biophysical parameters of IBM MoCs were only measurable at 48 and 96h (144h-constructs were broken) and showed abnormal strength and contraction dynamics (20%-reduced in IBM). TDP43 and HLA-I markers of degeneration and inflammation showed aberrant pattern expression. Mitochondrial function was conserved in IBM tissues in terms of lactate secretion and mitochondrial network but affected at functional level in COX/CS activity (55%-decreased at 144h; 0.18 vs. 0.40 AU) leading to higher maximal respiration (56%-increased at 48h; 655.44 vs 420.20 pmol/min/ug). Our findings indicate tissue degeneration and muscle impairment in IBM-MoCs, resembling some pathological features of disease at degenerative, inflammatory, and mitochondrial level. MoC technology is a robust platform to study IBM, paving the way to model the disease and foster therapeutics.