Myofibre-specific knockout of TGF-β type I receptors triggers muscle hypertrophy and promotes contraction and oxidative metabolism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1176687 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31095807.fastq.gz | Fastqsanger.gz | |||
| SRR31095808.fastq.gz | Fastqsanger.gz | |||
| SRR31095809.fastq.gz | Fastqsanger.gz | |||
| SRR31095810.fastq.gz | Fastqsanger.gz | |||
| SRR31095811.fastq.gz | Fastqsanger.gz |
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Project description:Transforming growth factor-β (TGF-β) signaling is associated with progressive skeletal muscle wasting and fibrosis, while double knockout of TGF-β type I receptors Acvr1b and Tgfbr1 results in hypertrophy. Gaining insights in how myofibre-specific knockout of these receptors affects muscle transcriptome, strength and mitochondrial activity could aid in the development of therapeutic interventions to improve muscle function. Here, we show that 3 months of myofibre-specific knockout of both receptors (dKO) in mice induced a 1.6-fold increase in gastrocnemius medialis mass and a 1.3-fold increase in maximal force. Soleus muscle mass and maximal force both increased 1.2-fold in dKO mice. Muscle hypertrophy in dKO mice was accompanied by a proportional increase in succinate dehydrogenase enzyme activity. Single receptor knockout caused minor phenotypical alterations. Transcriptome analyses revealed that gastrocnemius medialis had 1811 and soleus had 295 differentially expressed genes, mainly related to muscle contraction, hypertrophy, filament organization and oxidative metabolism. Hgf and Sln genes were strongly upregulated in both muscles of dKO mice, while Sntb1 was downregulated. This in combination of transcriptional changes are associated with muscle hypertrophy and increased mitochondrial biosynthesis. Our study highlights that myofibre-specific interference with both TGF-β type I receptors concurrently stimulates myofibre hypertrophy and mitochondrial activity.
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Project description:RNA-Seq analysis of mouse cardiac transcriptome. Transverse aortic contraction was used to induce cardiac hypertrophy (TAC). To compare wild type and physiological cardiac hypertrophy 'Sendetary' (feeding mouse during 4 weeks) and 'Swim (exercise training to induce the cardiac hypertrophy) samples were analysed.
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Project description:Background: Cardiac Ryanodine receptors (RyR2) can regulate Ca2+ release in the excitation-contraction coupling, when activated, it releases a large amount of Ca2+ into the cytoplasm. Additionally, studies have shown that dantrolene (a RyR2 inhibitor) protects against heart failure and arrhythmias by inhibiting domain decompression, Ca2+ leakage and diastolic Ca2+ sparking. However, the role and mechanism of dantrolene in cardiac hypertrophy remain unclear. Objective: In this study, we aimed to evaluate the therapeutic effects of dantrolene on pressure overload-induced cardiac hypertrophy in mice models by transverse aortic contraction (TAC) surgery and to explore its potential mechanism. Methods: C57/B6 mice (age: 8 weeks) underwent TAC or sham surgical procedure and were administered oral dantrolene (30 mg/kg) or the solvent drug postoperatively. After 4 weeks of drug treatment, RNA sequencing of mice left ventricle was performed.qRT–PCR validation was performed using SYBR Green assays. Results: We found that dantrolene significantly alleviated TAC-induced cardiac hypertrophy. According to RNA sequencing, 184 down-regulated genes were found after dantrolene treatment compared with TAC group, 8 of these were validated with qRT–PCR. According to the KEGG analysis, Creb3l3, IL18R1 and Ccl5 were down-regulated after dantrolene treatment, which were related to TNF-α pathway. Conclusion: As a RyR2 inhibitor, dantrolene attenuates cardiac hypetrophy through downregulating the TNF-α/NF-κB/NLRP3 signaling pathway.
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Project description:In our chemogenetic neurovacular mouse model, DRGs transcriptomic analysis was performed by RNA-seq; Oxidative stress is associated with cardiovascular and neurodegenerative disease. We created transgenic chemogenetic mouse lines expressing yeast D-amino oxidase (DAAO) in endothelial cells and neurons. DAAO generates hydrogen peroxide (H2O2) in target tissues when mice are provided with D-amino acids, causing oxidative stress. DAAO-TGCdh5 transgenic mice express DAAO under control of the putatively endothelial-specific Cdh5 promoter. We provided these mice with D-alanine¬– expecting a vascular phenotype– but found that the mice develop sensory ataxia and neurodegeneration in dorsal root ganglia (DRG), associated with transgene expression within DRG neurons; electron microscopy revealed distorted mitochondria. DAAO-TGCdh5 mice also develop cardiac hypertrophy in response to chemogenetic oxidative stress, and we discovered transgene expression in parasympathetic nodose ganglia innervating the heart. We developed and characterized another transgenic line expressing DAAO under control of a different endothelial cell-specific Tie2 promoter. DAAO-TGTie2 mice express the transgene in endothelium but not neurons, and develop neither ataxia nor cardiac hypertrophy. The combination of ataxia, mitochondrial dysfunction, and cardiac hypertrophy is similar to findings in patients with Friedreich's Ataxia. Our observations confirm that neurovascular oxidative stress is sufficient to cause sensory ataxia and cardiac hypertrophy, and identify the DAAO-TGCdh5 mouse as a potentially informative animal model for Friedreich’s Ataxia.
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