eng This thesis investigates the innovation and application of three-dimensional (3D) in vitro skeletal muscle tissue models to study and model muscle pathophysiology, particularly in idiopathic and corticosteroid-induced myopathies. Based on the historical evolution of cell culture techniques, this work highlights the limitations of conventional two-dimensional systems in reproducing native muscle structure, bioenergetics, and functional features. In the first section of this work, 3D human skeletal muscle constructs were developed using human muscle progenitor cells and exposed these tissues to sera from patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID (LC-19). Structural, functional and transcriptomic analyses post-treatment revealed disease-specific, time-dependent disturbances in mitochondrial function, protein homeostasis, and inflammatory signaling. The disease pathology in these models demonstrated mitochondrial stress, IL-6–mediated catabolism, and metabolic reprogramming toward glycolysis, with ME/CFS samples showing particularly severe contractile deficits. In the second part, a steroid myopathy model was produced by exposing 3D muscle tissues to dexamethasone. Taurine supplementation effectively restored contractile function by promoting protein synthesis and suppressing proteolysis by regulating the AKT/mTOR pathway modulation, even in the continued presence of dexamethasone. Together, these models provide powerful platforms for investigating disease mechanisms and testing therapeutic interventions, offering new mechanistic insights into muscle dysfunction. These insights are particularly important in conditions with unknown etiologies. Future prospects include developing an in vitro construct together with immune and neural components, increasing patient cohorts, and improving these models for clinical translation, particularly for testing patient stratification.
Sheeza Mughal (Tue,) studied this question.