Abstract:Desmin, the muscle-specific intermediate filament protein, is one of the earliest markers expressed in all muscle tissues during development. It forms a three-dimensional scaffold around the myofibril Z-disc and connects the entire contractile apparatus to the subsarcolemmal cytoskeleton, the nuclei and other cytoplasmic organelles. Desmin is essential for tensile strength and muscle integrity. In humans, disorganization of the desmin network is associated with cardiac and/or skeletal myopathies characterized … Show more
“…They have been diagnosed with a heterozygous pathogenic variant in the DES gene, namely a G-to-A transition at c.1315 (codon 439) in exon 8, which resulted in a substitution of glutamic acid by lysine in position 439 ( DES E439K ) at the C-terminal end of desmin. Such replacement of a negatively charged amino acid by a positively charged one is considered as a pathological modification that can affect desmin structure and its interactome [ 27 , 28 ]. Fig.…”
Background
Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients affected by desmin mutations remain unclear due in part, to the lack of relevant human cardiomyocyte models.
Methods
To shed light on the role of mitochondria in these mechanisms, we investigated cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DESE439K mutation that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cardiomyocytes were either cultured on an anisotropic micropatterned surface to obtain elongated and aligned cardiomyocytes, or as a cardiac spheroid to create a micro-tissue. Moreover, when applicable, results from cardiomyocytes were confirmed with heart biopsies of suddenly died patient of the same family harboring DESE439K mutation, and post-mortem heart samples from five control healthy donors.
Results
The heterozygous DESE439K mutation leads to dramatic changes in the overall cytoarchitecture of cardiomyocytes, including cell size and morphology. Most importantly, mutant cardiomyocytes display altered mitochondrial architecture, mitochondrial respiratory capacity and metabolic activity reminiscent of defects observed in patient’s heart tissue. Finally, to challenge the pathological mechanism, we transferred normal mitochondria inside the mutant cardiomyocytes and demonstrated that this treatment was able to restore mitochondrial and contractile functions of cardiomyocytes.
Conclusions
This work highlights the deleterious effects of DESE439K mutation, demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens up new potential therapeutic perspectives for this disease.
“…They have been diagnosed with a heterozygous pathogenic variant in the DES gene, namely a G-to-A transition at c.1315 (codon 439) in exon 8, which resulted in a substitution of glutamic acid by lysine in position 439 ( DES E439K ) at the C-terminal end of desmin. Such replacement of a negatively charged amino acid by a positively charged one is considered as a pathological modification that can affect desmin structure and its interactome [ 27 , 28 ]. Fig.…”
Background
Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients affected by desmin mutations remain unclear due in part, to the lack of relevant human cardiomyocyte models.
Methods
To shed light on the role of mitochondria in these mechanisms, we investigated cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DESE439K mutation that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cardiomyocytes were either cultured on an anisotropic micropatterned surface to obtain elongated and aligned cardiomyocytes, or as a cardiac spheroid to create a micro-tissue. Moreover, when applicable, results from cardiomyocytes were confirmed with heart biopsies of suddenly died patient of the same family harboring DESE439K mutation, and post-mortem heart samples from five control healthy donors.
Results
The heterozygous DESE439K mutation leads to dramatic changes in the overall cytoarchitecture of cardiomyocytes, including cell size and morphology. Most importantly, mutant cardiomyocytes display altered mitochondrial architecture, mitochondrial respiratory capacity and metabolic activity reminiscent of defects observed in patient’s heart tissue. Finally, to challenge the pathological mechanism, we transferred normal mitochondria inside the mutant cardiomyocytes and demonstrated that this treatment was able to restore mitochondrial and contractile functions of cardiomyocytes.
Conclusions
This work highlights the deleterious effects of DESE439K mutation, demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens up new potential therapeutic perspectives for this disease.
“…They have been diagnosed with a heterozygous pathogenic variant in the DES gene, namely a G-to-A transition at c.1315 (codon 439) in exon 8, which resulted in a substitution of glutamic acid by lysine in position 439 (DES E439K ) at the C-terminal end of desmin. Such replacement of a negatively charged amino acid by a positively charged one is considered as a pathological modification that can affect desmin structure and its interactome 27,28 . Generation of an isogenic pair.…”
“…They have been diagnosed with a heterozygous pathogenic variant in the DES gene, namely a G-to-A transition at c.1315 (codon 439) in exon 8, which resulted in a substitution of glutamic acid by lysine in position 439 ( DES E439K ) at the C-terminal end of desmin. Such replacement of a negatively charged amino acid by a positively charged one is considered as a pathological modification that can affect desmin structure and its interactome(Chourbagi et al , 2011; Joanne et al , 2011).…”
Beyond the observed alterations in cellular structure and mitochondria, the cellular mechanisms linking genetic mutations to the development of heart failure in patients affected by desmin defects remain unclear due, in part, to the lack of relevant human cardiomyocyte models. We investigated the role of mitochondria using cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DES-E439K desmin mutation, that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cells were either cultured on an anisotropic surface to obtain elongated and aligned cardiomyocytes, or as spheroids to create a micro-tissue. When applicable, results were confirmed with heart biopsies from the family harboring DES-E439K mutation. We show that mutant cardiomyocytes reproduce critical defects in mitochondrial architecture, respiratory capacity and metabolic activity as observed in patient's heart tissue. To challenge the pathological mechanism, normal mitochondria were transferred inside the mutant cardiomyocytes. This treatment restored mitochondrial and contractile functions. This work demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens-up new potential therapeutic perspectives.
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