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Developmentally regulated alternative splicing is perturbed in type 1 diabetic skeletal muscle.

ABSTRACT: INTRODUCTION:Type 1 diabetic patients can develop skeletal muscle weakness and atrophy by molecular mechanisms that are not well understood. Alternative splicing (AS) is critical for gene expression in the skeletal muscle, and its dysregulation is implicated in muscle weakness and atrophy. Therefore, we investigated whether AS patterns are affected in type 1 diabetic skeletal muscle contributing to skeletal muscle defects. METHODS:AS patterns were determined by reverse transcription-polymerase chain reaction and levels of RNA binding proteins were assessed by Western blot in type 1 diabetic mouse skeletal muscle and during normal mouse skeletal muscle development. RESULTS:Five genes with critical functions in the skeletal muscle are misspliced in type 1 diabetic skeletal muscle, resembling their AS patterns at embryonic stages. AS of these genes undergoes dramatic transitions during skeletal muscle development, correlating with changes in specific RNA binding proteins. CONCLUSION:Embryonic spliced variants are inappropriately expressed in type 1 diabetic skeletal muscle. Muscle Nerve 56: 744-749, 2017.

SUBMITTER: Nutter CA

PROVIDER: S-EPMC5704903 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Developmentally regulated alternative splicing is perturbed in type 1 diabetic skeletal muscle.

Nutter Curtis A CA Jaworski Elizabeth E Verma Sunil K SK Perez-Carrasco Yareli Y Kuyumcu-Martinez Muge N MN

Muscle & nerve 20170417 4

<h4>Introduction</h4>Type 1 diabetic patients can develop skeletal muscle weakness and atrophy by molecular mechanisms that are not well understood. Alternative splicing (AS) is critical for gene expression in the skeletal muscle, and its dysregulation is implicated in muscle weakness and atrophy. Therefore, we investigated whether AS patterns are affected in type 1 diabetic skeletal muscle contributing to skeletal muscle defects.<h4>Methods</h4>AS patterns were determined by reverse transcripti ...[more]

PMID: 28164326

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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.

Dataset Information

Developmentally regulated alternative splicing is perturbed in type 1 diabetic skeletal muscle.

Publications

Developmentally regulated alternative splicing is perturbed in type 1 diabetic skeletal muscle.

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