The skeletal muscle circadian clock regulates titin splicing through RBM20

Riley, Lance A.; Zhang, Xiping; Douglas, Collin M; Mijares, Joseph M; Hammers, David W.; Wolff, Christopher A.; Wood, Neil B.; Olafson, Hailey; Du, Ping; Labeit, Siegfried; Previs, Michael J.; Wang, Eric T.; Esser, Karyn A.

doi:10.7554/elife.76478

Cited by 12 publications

(9 citation statements)

References 50 publications

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“…In relation to sarcomeric proteins, we found RBM20 enriched in all 4 MTJ subclusters (Supplementary Data S1). RBM20 is a potent regulator of titin splicing (Riley et al 2022), which suggests structural specialization of the myofibre tips at the level of the sarcomere.…”

Section: Discussionmentioning

confidence: 99%

Distinct myofibre domains of the human myotendinous junction revealed by single nucleus RNA-seq

Karlsen

Yeung

Schjerling

et al. 2022

Preprint

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The myotendinous junction (MTJ) is a specialized domain of the multinucleated myofibre, faced with the challenge of maintaining robust cell-matrix contact with the tendon under high mechanical stress and strain. Here, we profiled 24,161 nuclei in semitendinosus muscle-tendon samples from 3 healthy males by single nucleus RNA-sequencing (snRNA-seq), alongside spatial transcriptomics, to gain insight into the genes characterizing this specialization in humans. We identified a cluster of MTJ myonuclei, represented by 47 enriched transcripts, of which the presence of ABI3BP, ABLIM1, ADAMTSL1, BICD1, CPM, FHOD3, FRAS1 and FREM2 was confirmed at the MTJ at the protein level by immunofluorescence. Four distinct subclusters of MTJ myonuclei were apparent and segregated into two COL22A1-expressing subclusters and two lacking COL22A1 but with a clear fibre type profile expressing MYH7 or MYH1/2. Our findings reveal distinct myonuclei profiles of the human MTJ, a weak link in the musculoskeletal system, which is selectively affected in pathological conditions, from muscle strains to muscular dystrophies.

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Section: Discussionmentioning

confidence: 99%

Distinct myofibre domains of the human myotendinous junction revealed by single nucleus RNA-seq

Karlsen

Yeung

Schjerling

et al. 2022

Preprint

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“…By knocking out RBM20, researchers found that LDB3 exon 4 and exons 5/6 are mutually exclusive and are regulated by RBM20. 14,29,30 We suspect that LDB3 is also regulated by RBM20 in chicken skeletal muscle. Previous research has shown that RBM20 recognizes target genes mainly via its RRM domains.…”

Section: ■ Discussionmentioning

confidence: 94%

Divergent Regulatory Roles of Transcriptional Variants of the Chicken LDB3 Gene in Muscle Shaping

Wei,

Niu,

Chen

et al. 2024

J. Agric. Food Chem.

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LIM domain binding 3 (LDB3) serves as a striated muscle-specific Z-band alternatively spliced protein that plays an important role in mammalian skeletal muscle development, but its regulatory role and molecular mechanism in avian muscle development are still unclear. In this study, we reanalyzed RNA sequencing data sets of 1415 samples from 21 chicken tissues published in the NCBI GEO database. First, three variants (LDB3-X, LDB3-XN1, and LDB3-XN2) generated by alternative splicing of the LDB3 gene were identified in chicken skeletal muscle, among which LDB3-XN1 and LDB3-XN2 are novel variants. LDB3-X and LDB3-XN1 are derived from exon skipping in chicken skeletal muscle at the E18-D7 stage and share three LIM domains, but LDB3-XN2 lacks a LIM domain. Our results preliminarily suggest that the formation of three variants of LDB3 is regulated by RBM20. The three splice isomers have divergent functions in skeletal muscle according to in vitro and in vivo assays. Finally, we identified the mechanism by which different variants play different roles through interactions with IGF2BP1 and MYHC, which promote the proliferation and differentiation of chicken myoblasts, in turn regulating chicken myogenesis. In conclusion, this study revealed the divergent roles of three LDB3 variants in chicken myogenesis and muscle remodeling and demonstrated their regulatory mechanism through protein−protein interactions.

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“…We studied the effect of estrogen manipulation on the skeletal muscle proteome using an untargeted proteomic approach with TMT-labelling and demonstrated that estrogen levels modulate the expression of RNA binding motif factor 20 (Rbm20). Since Rbm20 is regulated by the muscle molecular clock program 32 , our data suggest that estrogen depletion alters mitochondrial metabolism potentially through modulating the muscle circadian rhythm.…”

Section: Introductionmentioning

confidence: 83%

“…Recently, Rbm20 was shown to regulate Ttn splicing in skeletal muscle under the control of the muscle circadian clock regulatory genes, Bmal1 and Clock 32 . There is well-established reciprocal regulation between circadian and estrogen signaling (for a review, see Alvord et al , 2022 83 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

Timpani,

Debrincat,

Kourakis

et al. 2024

Preprint

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Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates and citrate synthase activity but that these deficits can be offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggests that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.

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The skeletal muscle circadian clock regulates titin splicing through RBM20

Cited by 12 publications

References 50 publications

Distinct myofibre domains of the human myotendinous junction revealed by single nucleus RNA-seq

Distinct myofibre domains of the human myotendinous junction revealed by single nucleus RNA-seq

Divergent Regulatory Roles of Transcriptional Variants of the Chicken LDB3 Gene in Muscle Shaping

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

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