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Assessment of the molecular consequences associated with loss of dysferlin expression in hiPSC-derived muscle cells from LGMD R2 patients.

ABSTRACT: LGMD R2 is a rare genetic disorder characterized by progressive proximal muscle weakness and wasting caused by a recessive loss of function of dysferlin, a transmembrane protein controlling plasma membrane repair in skeletal muscles. Despite major advances in biotherapies in recent years, there is currently no curative treatment available for LGMD R2, or dysferlinopathies in general. This failure can be explained in part by our lack of understanding of the functions performed by dysferlin within the muscle fiber. Indeed, despite the identification of dysferlin's role in membrane repair, intracellular vesicular trafficking or calcium homeostasis, we do not know which of these functions or combination of functions is most involved in the pathophysiological development of dysferlinopathies. It also seems highly likely that other dysferlin functions have yet to be discovered. In this aim, we generated hiPSC-derived skeletal muscle model and investigated the molecular consequences associated with loss of dysferlin expression by performing a comparative gene expression profiling between control and LGMD R2 myotubes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261832 | GEO | 2026/01/12

REPOSITORIES: GEO

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Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.

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Assessment of the molecular consequences associated with loss of dysferlin expression in hiPSC-derived muscle cells from LGMD R2 patients.

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