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CAPN3 depletion causes continuously activated innate immune response in zebrafish

ABSTRACT: Capn3 is responsible for human disease LGMD2B, but the mechanism is largely unknown. We generated two capn3b-/- mutant zebrafish alleles and found that p53 is highly enriched in the hepatocyte nucleoli of capn3b knock-out fish. Although homozygous capn3b knock-out mutants are viable and fertile, they display shorter length and lateral curvature phenotype in adulthood, which is similar to the limb-girdle muscular dystrophy type 2A (LGMD2A) patients caused by capn3 mutation. Using RNA-seq analysis of adult liver, we identified differentially expressed genes in capn3b-/- mutants. Genes involved in innate immune response pathways were highly enriched in the mutants' livers. This study presents the connection between capn3 deficiency and immune defects and provides new insights into LGMD2B therapy.

ORGANISM(S): Danio rerio

PROVIDER: GSE198711 | GEO | 2024/03/07

REPOSITORIES: GEO

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Project description:Limb-girdle muscular dystrophies (LGMD) is a group of muscle diseases characterized by pro-gressive muscle weakness and muscular atrophy of proximal muscles. Limb-girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a specific LGMD caused by a gene mutation encoding the calcium-dependent neutral cysteine protease calpain-3 (CAPN3). In our previous study, a novel compound heterozygous mutation, c.635T>C causing missense mu-tation of p.Leu212Pro, was identified in LGMDR1 patients. For the investigation of the molecular mechanism for muscular dystrophy, LGMDR1 CAPN3-point-mutation mouse model was pre-pared by injecting into fertilized eggs of C57 mice the following: in vitro transcribed Cas9 mRNA, sgRNA for mutation sites, and homologous fragments. The LGMDR1 models displayed a mild and slow malnutrition phenotype until 10 months old. Western blot and immunofluorescence assay also showed that the expression level of CAPN3 protein in muscle tissue of mutant mice was similar to that of wild-type mice. Pathological results revealed that a few inflammatory cells infiltrated the endomyocytes of some homozygous mice at 10 months of age. Compared with wild-type mice, motor function was not significantly impaired in CAPN3 mutant mice. Interest-ingly, we found that the arrangement and ultrastructural alterations of mitochondria in the muscular tissue of homozygous mice at the electron microscopy level. Then, muscle regeneration of LGMDR1 was simulated using Cardiotoxin (CTX) to induce muscle necrosis and regeneration to trigger the injury modification process. A large number of inflammatory cells and damaged myofibers were observed in both mutant mice and wild type mice 3 and 6 days after CTX treat-ment. Fifteen and twenty-one days after treatment, the repair of diseased mice was significantly worse than that of control mice. RNA-seq results demonstrated that the expression of mito-chondrial-related functional genes was significantly down-regulated in mutant mice. Taken to-gether, our results strongly suggest that LGMDR1 mouse model with a novel c.635T >C mutation in CAPN3 gene was significant disfunction in muscle injury repair through impairing the mito-chondrion.

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CAPN3 depletion causes continuously activated innate immune response in zebrafish

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