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ABSTRACT: CRISPR-Cas9 mediated endogenous utrophin modulation improves Duchenne Muscular Dystrophy

PROVIDER: PRJNA941216 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23731000_1.fastq.gz	Fastqsanger.gz
	SRR23731000_2.fastq.gz	Fastqsanger.gz
	SRR23731100_1.fastq.gz	Fastqsanger.gz
	SRR23731100_2.fastq.gz	Fastqsanger.gz
	SRR23731001_1.fastq.gz	Fastqsanger.gz

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Project description:Transcriptional adaptation drives utrophin upregulation in Duchenne muscular dystrophy

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Non-steroidal mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy

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Project description:Skeletal muscle wasting results from numerous pathological conditions impacting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss of function models combined with in vivo cell biology and proteomic approaches, we identified the endoplasmic reticulum chaperone, BiP, as a novel target of the E3 ubiquitin ligase atrogin-1. A loss in atrogin-1 results in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fibre integrity. We further implicate a disruption in atrogin-1 mediated BiP regulation in the pathogenesis of Duchenne Muscular Dystrophy. We reveal that BiP is not only upregulated in Duchenne Muscular Dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorates pathology in a zebrafish model of Duchenne Muscular Dystrophy. Collectively, our data implicates a novel disease axis in the pathogenesis of Duchenne Muscular Dystrophy, and highlights atrogin-1’s essential role in maintaining muscle homeostasis.

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