Facioscapulohumeral dystrophy weakened sarcomeric contractility is mimicked in induced pluripotent stem cells‐derived innervated muscle fibres

Abstract

Background Facioscapulohumeral dystrophy (FSHD) is a late-onset autosomal dominant form of muscular dystrophy involving specific groups of muscles with variable weakness that precedes inflammatory response, fat infiltration, and muscle atrophy. As there is currently no cure for this disease, understanding and modelling the typical muscle weakness in FSHD remains a major milestone towards deciphering the disease pathogenesis as it will pave the way to therapeutic strategies aimed at correcting the functional muscular defect in patients. Methods To gain further insights into the specificity of the muscle alteration in this disease, we derived induced pluripotent stem cells from patients affected with Types 1 and 2 FSHD but also from patients affected with Bosma arhinia and microphthalmia. We differentiated these cells into contractile innervated muscle fibres and analysed their transcriptome by RNA Seq in comparison with cells derived from healthy donors. To uncover biological pathways altered in the disease, we applied MOGAMUN, a multi-objective genetic algorithm that integrates multiplex complex networks of biological interactions (protein-protein interactions, co-expression, and biological pathways) and RNA Seq expression data to identify active modules. Results We identified 132 differentially expressed genes that are specific to FSHD cells (false discovery rate < 0.05). In FSHD, the vast majority of active modules retrieved with MOGAMUN converges towards a decreased expression of genes encoding proteins involved in sarcomere organization (P value 2.63e À12 ), actin cytoskeleton (P value 9.4e À5 ), myofibril (P value 2.19e À12 ), actin-myosin sliding, and calcium handling (with P values ranging from 7.9e À35 to 7.9e À21 ). Combined with in vivo validations and functional investigations, our data emphasize a reduction in fibre contraction (P value < 0.0001) indicating that the muscle weakness that is typical of FSHD clinical spectrum might be associated with dysfunction of calcium release (P value < 0.0001), actin-myosin interactions, motor activity, mechano-transduction, and dysfunctional sarcomere contractility. Conclusions Identification of biomarkers of FSHD muscle remain critical for understanding the process leading to the pathology but also for the definition of readouts to be used for drug design, outcome measures, and monitoring of therapies. The different pathways identified through a system biology approach have been largely overlooked in the disease. Overall, our work opens new perspectives in the definition of biomarkers able to define the muscle alteration but also in the development of novel strategies to improve muscle function as it provides functional parameters for active molecule screening.

SMCHD1 genetic variants in type 2 FacioScapuloHumeral dystrophy and challenges in predicting pathogenicity and disease penetrance.

“…The pleiotropic impact of SMCHD1 variants or haploinsu ciency remains a key question to understand how variants in the same gene might lead to at least four different syndromes, 4,15,[17][18][19] in which D4Z4 hypomethylation but also DUX4 expression are consistently observed 17,18,35,[41][42][43] . In FSHD2, SMCHD1 variants were previously located around the ATP binding site or on a loop adjacent to the ATP binding pocket 23 .…”

Assessing Facioscapulohumeral Muscular Dystrophy through Comparative Analysis of Bulk and Single-Cell Transcriptomes

“…IGFBP7 is linked to insulin-like growth factor pathways and cell growth regulation [6]. FN1 is involved in cell-adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, and metastasis [7]. CCN2 is a mitogen secreted by vascular endothelial cells and plays a role in chondrocyte proliferation and differentiation, as well as cell adhesion in many cell types [8].…”

Unlocking the Treatment of Facioscapulohumeral Muscular Dystrophy Type 2: The Bisphenol Connection

“…IGFBP7 is associated with pathways involving insulin-like growth factors and cell growth regulation [3]. FN1 participates in various cellular processes such as cell adhesion and migration, crucial in embryogenesis, wound healing, blood coagulation, host defense, and metastasis [4]. CCN2, secreted by vascular endothelial cells, acts as a mitogen influencing chondrocyte proliferation and differentiation, as well as cell adhesion in diverse cell types [5].…”