KDM5A drives ageing signatures and disturbed muscle regeneration in sporadic Inclusion Body Myositis: from the deep proteome towards disease models and novel therapies;

Sporadic Inclusion Body Myositis (sIBM) is the most common myopathy above the age of 50 years and is presumed to be an acquired disorder. The interplay of potential mechanisms underlying sIBM pathogenesis remains unclear as is illustrated by a dual inflammatory-degenerative pathology in the affected muscle. Due to lack of effective therapy, steady decline of muscle strength results in loss of ambulation and ultimately reduced life expectancy. The uncertainty concerning the key pathomechanisms complicates the design of reliable experimental cell- or animal-models, emphasizing the relevance of well-designed experiments using human disease tissue. Capitalizing on the availability of patient disease-tissue under the form of diagnostic muscle biopsies, we established a unique (in house performed) high-resolution proteomics study, assessing the proteome of muscle lysates of 28 sIBM patients and 28 matched control individuals. This dataset provided unique insights in the proteomic landscape of sIBM, captivating known core features of sIBM pathomechanisms as well as highlighting strong signatures pointing towards selective failure of myogenesis. We identified KDM5A as a key upstream driver of sIBM pathology, interconnecting the DNA damage pathway, regulation of cell cycle and differentiation and energy homeostasis in sIBM skeletal muscle. The central aim of this project is to gather additional functional evidence that upregulation of KDM5A, a histone demethylase, is involved in sIBM pathomechanisms and failure of muscle regeneration in particular. Ultimately, the aim is working towards an actual therapy for sIBM, a currently untreatable and debilitating muscle disorder. Firstly, we will study KDM5A expression and activity and afterwards inhibition of KDM5A in immortalized human myoblast cell line with induced sIBM-like pathology. Secondly, we will study the effect of KDM5A overexpression in immortalized human myoblast cell lines from healthy middle-aged control individuals. Ultimately, we will establish immortalized patient-derived myoblasts from muscle as well as from induced Pluripotent Stem Cells (iPSC) and study the effect of KDM5A inhibition. This project could have major impact on the sIBM research field, by: 1) providing new mechanistic insights based on an alternative in vitro model not biased towards one of two general hypotheses; 2) resulting in a novel therapeutic strategy for sIBM. Furthermore, we aim to establish sIBM patient-derived immortalized myoblasts and iPSC differentiated into myotubes as a novel tools for further in vitro pathomechanistic and therapeutic studies.

Keywords:THERAPEUTICS, TRANSLATIONAL RESEARCH, NEUROMUSCULAR DISEASES

Disciplines:Pharmacotherapy, Neurological and neuromuscular diseases