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Rbm24 modulates adult skeletal muscle regeneration via regulation of alternative splicing

ABSTRACT: Rationale: The adult skeletal muscle can self-repair efficiently following mechanical or pathological damage due to its remarkable regenerative capacity. However, regulatory mechanisms underlying muscle regeneration are complicated and have not been fully elucidated. Alternative splicing (AS) is a major mechanism responsible for post-transcriptional regulation. Many aberrant AS events have been identified in patients with muscular dystrophy which is accompanied by abnormal muscle regeneration. However, little is known about the correlation between AS and muscle regeneration. It has been reported that RNA binding motif protein 24 (Rbm24), a tissue-specific splicing factor, is involved in embryo myogenesis while the role of Rbm24 in adult myogenesis (also called muscle regeneration) is poorly understood. Methods: To investigate the role of Rbm24 in adult skeletal muscle, we generated Rbm24 conditional knockout mice and satellite cell-specific knockout mice. Furthermore, a cardiotoxin (CTX)-induced injury model was utilized to assess the effects of Rbm24 on skeletal muscle regeneration. Genome-wide RNA-Seq was performed to identify the changes in AS following loss of Rbm24. Results: Rbm24 knockout mice displayed abnormal regeneration 4 months after tamoxifen treatment. Using RNA-Seq, we found that Rbm24 regulated a complex network of AS events involved in multiple biological processes, including myogenesis, muscle regeneration and muscle hypertrophy. Moreover, using a CTX-induced injury model, we showed that loss of Rbm24 in skeletal muscle resulted in myogenic fusion and differentiation defects and significantly delayed muscle regeneration. Furthermore, satellite cell-specific Rbm24 knockout mice recapitulated the defects in regeneration seen in the global Rbm24 knockout mice. Importantly, we demonstrated that Rbm24 regulated AS of Mef2d, Naca, Rock2 and Lrrfip1 which are essential for myogenic differentiation and muscle regeneration. Conclusions: The present study demonstrated that Rbm24 regulates dynamic changes in AS and is essential for adult skeletal muscle regeneration.

SUBMITTER: Zhang M

PROVIDER: S-EPMC7532667 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundAs the interest in manned spaceflight increases, so does the requirement to understand the transcriptomic mechanisms that underlay the detrimental physiological adaptations of skeletal muscle to microgravity. While microgravity-induced differential gene expression (DGE) has been extensively investigated, the contribution of differential alternative splicing (DAS) to the plasticity and functional status of the skeletal muscle transcriptome has not been studied in an animal model. Therefore, by evaluating both DGE and DAS across spaceflight, we set out to provide the first comprehensive characterization of the transcriptomic landscape of skeletal muscle during exposure to microgravity.MethodsRNA-sequencing, immunohistochemistry, and morphological analyses were conducted utilizing total RNA and tissue sections isolated from the gastrocnemius and quadriceps muscles of 30-week-old female BALB/c mice exposed to microgravity or ground control conditions for 9 weeks.ResultsIn response to microgravity, the skeletal muscle transcriptome was remodeled via both DGE and DAS. Importantly, while DGE showed variable gene network enrichment, DAS was enriched in structural and functional gene networks of skeletal muscle, resulting in the expression of alternatively spliced transcript isoforms that have been associated with the physiological changes to skeletal muscle in microgravity, including muscle atrophy and altered fiber type function. Finally, RNA-binding proteins, which are required for regulation of pre-mRNA splicing, were themselves differentially spliced but not differentially expressed, an upstream event that is speculated to account for the downstream splicing changes identified in target skeletal muscle genes.ConclusionsOur work serves as the first investigation of coordinate changes in DGE and DAS in large limb muscles across spaceflight. It opens up a new opportunity to understand (i) the molecular mechanisms by which splice variants of skeletal muscle genes regulate the physiological adaptations of skeletal muscle to microgravity and (ii) how small molecule splicing regulator therapies might thwart muscle atrophy and alterations to fiber type function during prolonged spaceflight.

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Rbm24 modulates adult skeletal muscle regeneration via regulation of alternative splicing

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