Benabides, M. | bioRxiv Science

bioRxiv2022

Skeletal muscle cells derived from induced pluripotent stem cells: a platform for limb girdle muscular dystrophies.

Limb girdle muscular dystrophies (LGMD), caused by mutations in 29 different genes, are the fourth most prevalent group of genetic muscle diseases, leading to progressive weakness and atrophy of the skeletal muscles. Although the link between LGMD and their genetic origins has been determined, LGMD still represent an unmet medical need. In this paper, we describe a platform for modeling LGMD based on the use of human induced pluripotent stem cells (hiPSC). Thanks to the self-renewing and pluripotency properties of hiPSC, this platform provides an alternative and renewable source of skeletal muscle cells (skMC) to primary, immortalized or overexpressing cells. We report that skMC derived from hiPSC express the majority of the genes and proteins causing LGMD. As a proof of concept, we demonstrate the importance of this cellular model for studying LGMDR9 by evaluating disease-specific phenotypes in skMC derived from hiPSC obtained from four patients.

cell biology↗

bioRxiv2022

Dual blockade of misfolded alpha-sarcoglycan degradation by bortezomib and givinostat combination

Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C--SG protein. We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C--SG degradation inhibition. Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.

pharmacology and toxicology↗