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Alternative splicing regulates the physiological adaptation of the mouse hind limb postural and phasic muscles to microgravity

ABSTRACT: We sought to comprehensively elucidate the transcriptomic underpinnings of microgravity-induced muscle phenotypes in mice by evaluating both differential gene expression (DGE) and changes in alternative splicing (AS) due to extended spaceflight. Total RNA was isolated from the gastrocnemius and quadriceps, postural and phasic muscles of the hind limb, respectively, of 32-week-old female BALB/c mice exposed to microgravity or ground control conditions for nine weeks. RNA sequencing revealed that DGE and AS varied across postural and phasic muscle types with preferential employment of DGE in the gastrocnemius and AS in the quadriceps. Gene ontology analysis indicated that DGE and AS regulate distinct molecular processes. Various non-differentially expressed transcripts encoding musculoskeletal proteins (Tnnt3, Tnnt1, Neb, Ryr1, and Ttn) and muscle-specific RNA binding splicing regulators (Mbnl1 and Rbfox1) were found to have significant changes in AS that altered critical functional domains of their protein products. In striking contrast, microgravity-induced differentially expressed genes were associated with translation/ribosomal function and lipid metabolism. Our work serves as the first comprehensive investigation of coordinate changes in DGE and AS in large limb muscles across spaceflight. We propose that substantial remodeling of pre-mRNA by AS is a major component of transcriptomic adaptation of skeletal muscle to microgravity. The alternatively spliced genes identified here could be targeted by small molecule splicing regulator therapies to address microgravity-induced changes in muscle during spaceflight.

ORGANISM(S): Mus musculus

PROVIDER: GSE178822 | GEO | 2021/06/25

REPOSITORIES: GEO

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Project description:Introduction: The mouse skeletal muscle is composed of four distinct fiber types that differ in contractile function, number of mitochondria and metabolism. Every muscle group has a specific composition and distribution of the four fiber types. Until now, three genes (CnA, PGC1α and PPARδ) are identified that are involved in the generation of more oxidative muscle types. In the present study we searched for novel genes that are involved in specifying different muscle types. Methods: Gastrocnemius and quadriceps muscles were dissected from 20-week old C57BL/6J mice. Gene expression profiles were compared at the level of the whole-transcriptome. The diet-sensitivity of genes differentially expressed between muscle types was explored by comparing mice fed a low fat diet with mice fed a high fat diet. Results: We identified 162 differentially expressed genes in the gastrocnemius as compared with the quadriceps. Genes with the strongest regulations were markers for oxidative fiber types, Hoxd8, Hoxd9 and Hoxd10 and others involved in embryogenesis. Additionally, diet did not influence the expression levels of genes specifying muscle types. Finally, when extrapolating our data to the soleus we could not find a corresponding gene expression pattern between Hoxd8, Hoxd9 and any of the fiber-type specific markers. However, based on these gene expression patterns we could distinguish the gastrocnemius, quadriceps and soleus from each other. Conclusion: Hoxd genes and genes that are markers for the different fiber types specify muscle type in a diet-independent way The aim of the present study was to find novel genes that may play a role in specifying muscle types. Therefore we compared gene expression profiles of the gastrocnemius with the quadriceps at the level of the whole-transcriptome. Functional implications were assessed by the analyses of predefined gene sets based on Gene Ontology, biochemical, metabolic and signaling pathways. muscle-type comparison

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Alternative splicing regulates the physiological adaptation of the mouse hind limb postural and phasic muscles to microgravity

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